Novel compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to novel antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel alkyl carboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

FIELD OF THE INVENTION

The present invention relates to novel antidiabetic, hypolipidemic,antiobesity and hypocholesterolemic compounds, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutically acceptable compositionscontaining them. More particularly, the present invention relates tonovel alkyl carboxylic acids of the general formula (I), theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutically acceptablecompositions containing them.

The present invention also relates to a process for the preparation ofthe above said compounds, their analogs, their derivatives, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates and pharmaceutical compositions containing them.

The present invention also relates to novel intermediates, processes fortheir preparation, their use in the preparation of compounds of formula(I) and their use as antidiabetic, hypolipidemic, antiobesity andhypocholesterolemic compounds.

The present invention also relates to novel intermediates, processes fortheir preparation and their use in the preparation of compounds offormula (I).

The compounds of the present invention lower plasma glucose,triglycerides, lower total cholesterol (TC) and increase high densitylipoprotein (HDL) and decrease low density lipoprotein (LDL), which havea beneficial effect on coronary heart disease and atherosclerosis.

The compounds of general formula (I) are useful in reducing body weightand for the treatment and/or prophylaxis of diseases such asatherosclerosis, stroke, peripheral vascular diseases and relateddisorders. These compounds are useful for the treatment ofhyperlipidemia, hyperglycemia, hypercholesterolemia, lowering ofatherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL.The compounds of the present invention can be used for the treatment ofcertain renal diseases including glomerulonephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. Thecompounds of general formula (I) are also useful for the treatmentand/or prophylaxis of leptin resistance, impaired glucose tolerance,disorders related to syndrome X such as hypertension, obesity, insulinresistance, coronary heart disease and other cardiovascular disorders.These compounds may also be useful as aldose reductase inhibitors, forimproving cognitive functions in dementia, treating diabeticcomplications, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS), inflammatory boweldiseases, osteoporosis, myotonic dystrophy, pancreatitis,arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammationand for the treatment of cancer. The compounds of the present inventionare also useful in the treatment and/or prophylaxis of the above saiddiseases in combination/concomittant with one or more HMG CoA reductaseinhibitor; cholesterol absorption inhibitor; antiobesity drug;lipoprotein disorder treatment drug; hypoglycemic agent; insulin;biguanide; sulfonylurea; thiazolidinedione; dual PPARα and γ agonists ora mixture thereof.

BACKGROUND OF THE INVENTION

Atherosclerosis and other peripheral vascular diseases effect thequality of life of millions of people. Therefore, considerable attentionhas been directed towards understanding the etiology ofhypercholesterolemia and hyperlipidemia and development of effectivetherapeutic strategies.

Hypercholesterolemia has been defined as plasma cholesterol level thatexceeds arbitrarily defined value called “normal” level. Recently, ithas been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in the general population andthe risk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with variouslipoproteins such as Low density lipoprotein (LDL), Intermediate densitylipoprotein (IDL), High density lipoprotein (HDL) and partially as Verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations, (Stampfer et al., N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

In CAD, generally “fatty streaks” in carotid, coronary and cerebralarteries, are found which are primarily free and esterified cholesterol.Miller et al, (Br. Med. J, 282 (1981), 1741-1744) have shown thatincrease in HDL-particles may decrease the number of sites of stenosisin coronary arteries of human, and high level of HDL-cholesterol mayprotect against the progression of atherosclerosis. Picardo et al,Arteriosclerosis 6 (1986) 434-441 have shown by in vitro experiment thatHDL is capable of removing cholesterol from cells. They suggest that HDLmay deplete tissues of excess free cholesterol and transfer it to liver,which is known as reverse cholesterol transport, (Macikinnon et al., J.Biol. chem. 261 (1986), 2548-2552). Therefore, agents that increase HDLcholesterol would have therapeutic significance for the treatment ofhypercholesterolemia and coronary heart diseases (CHD).

Obesity is a disease highly prevalent in affluent societies and in thedeveloping world and is a major cause of morbidity and mortality. It isa state of excess body fat accumulation. The causes of obesity areunclear. It is believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression have been a part of obesity treatment. There is a need forefficient therapy to fight this disease since it may lead to coronaryheart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

Diabetes and insulin resistance is yet another disease which severelyeffects the quality of large population in the world. Insulin resistanceis the diminished ability of insulin to exert its biological actionacross a broad range of concentrations. In insulin resistance, the bodysecretes abnormally high amounts of insulin to compensate for thisdefect; failing which, the plasma glucose concentration inevitablyraises and develops into diabetes. Among the developed countries,diabetes mellitus is a common problem and is associated with a varietyof abnormalities including obesity, hypertension, hyperlipidemia (J.Clin. Invest., 75 (1985) 809-817; N. Engl. J. Med 317 (1987) 350-357; J.Clin. Endocrinol. Metab., 66 (1988) 580-583; J. Clin. Invest., 68 (1975)957-969) and other renal complications (patent publication No. WO95/21608). It is now increasingly being recognized that insulinresistance and relative hyperinsulinemia have a contributory role inobesity, hypertension, atherosclerosis and type 2 diabetes mellitus. Theassociation of insulin resistance with obesity, hypertension and anginahas been described as a syndrome having insulin resistance as thecentral pathogenic link-Syndrome-X.

Hyperlipidemia is the primary cause for cardiovascular (CVD) and otherperipheral vascular diseases. High risk of CVD is related to the higherLDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein)seen in hyperlipidemia. Patients having glucose intolerance/insulinresistance in addition to hyperlipidemia have higher risk of CVD.Numerous studies in the past have shown that lowering of plasmatriglycerides and total cholesterol, in particular LDL and VLDL andincreasing HDL cholesterol help in preventing cardiovascular diseases.

Peroxisome proliferator activated receptors (PPAR) are members of thenuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) hasbeen implicated in regulating differentiation of adipocytes(Endocrinology, 135 (1994) 798-800) and energy homeostasis (Cell, 83(1995) 803-812), whereas the alpha (α) isoform of PPAR (PPARα) mediatesfatty acid oxidation (Trend Endocrin. Metab., 4 (1993) 291-296) therebyresulting in reduction of circulating free fatty acid in plasma (CurrentBiol. 5 (1995) 618-621). PPARα agonists have been found useful for thetreatment of obesity (WO 97/36579). It has been recently disclosed thatcompounds which are agonists for both PPARα and PPARγ are suggested tobe useful for the treatment of syndrome X (WO 97/25042). Similar effectbetween the insulin sensitizer (PPARγ agonist) and HMG CoA reductaseinhibitor has been observed which may be useful for the treatment ofatherosclerosis and xanthoma (EP 0 753 298).

It is known that PPARγ plays an important role in adipocytedifferentiation (Cell, 87 (1996) 377-389). Ligand activation of PPAR issufficient to cause complete terminal differentiation (Cell, 79 (1994)1147-1156) including cell cycle withdrawal. PPARγ is consistentlyexpressed in certain cells and activation of this nuclear receptor withPPARγ agonists would stimulate the terminal differentiation of adipocyteprecursors and cause morphological and molecular changes characteristicsof a more differentiated, less malignant state (Molecular Cell, (1998),465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., 94(1997) 237-241) and inhibition of expression of prostate cancer tissue(Cancer Research 58 (1998) 3344-3352). This would be useful in thetreatment of certain types of cancer, which express PPARγ and could leadto a quite nontoxic chemotherapy.

Leptin resistance is a condition wherein the target cells are unable torespond to leptin signal. This may give rise to obesity due to excessfood intake and reduced energy expenditure and cause impaired glucosetolerance, type 2 diabetes, cardiovascular diseases nd such otherinterrelated complications. Kallen et al (Proc. Natl. Acad. Sci. (1996)93, 5793-5796) have reported that insulin sensitizers which perhaps dueto the PPAR agonist expression lower plasma leptin concentrations.However, it has been recently disclosed that compounds having insulinsensitizing property also possess leptin sensitization activity. Theylower the circulating plasma leptin concentrations by improving thetarget cell response to leptin (WO 98/02159).

A few alkyl carboxylic acids, their derivatives and their analogs havebeen reported to be useful in the treatment of hyperglycemia andhypercholesterolemia. Some of such compounds described in the prior artare outlined below:

-   i). In our international publication No. WO 99/08501 we have    disclosed the compounds of general formula (IIa)    where X represents O or S; the groups R¹, R² and group R³ when    attached to the carbon atom, may be same or different and represent    hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally    substituted groups selected from alkyl, cycloalkyl, alkoxy,    cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,    heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,    acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino,    aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,    aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl,    alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,    aralkoxycarbonylamino, carboxylic acid or its derivatives, or    sulfonic acid or its derivatives; R¹, R² along with the adjacent    atoms to which they are attached may also form a 5-6 membered    substituted or unsubstituted cyclic structure containing carbon    atoms with one or more double bonds, which may optionally contain    one or more heteroatoms selected from oxygen, nitrogen and sulfur;    R³ when attached to nitrogen atom represents hydrogen, hydroxy,    formyl or optionally substituted groups selected from alkyl,    cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,    heteroaryl, heteroaralkyl, acyl acyloxy, hydroxyalkyl, amino,    acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,    aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,    aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,    aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid    derivatives, or sulfonic acid derivatives; the linking group    represented by —(CH₂)_(n)—O— may be attached either through nitrogen    atom or through carbon atom where n is an integer ranging from 1-4;    Ar represents an optionally substituted divalent single or fused    aromatic or heterocyclic group; R⁴ represents hydrogen atom,    hydroxy, alkoxy, halogen, lower alkyl, optionally substituted    aralkyl group or forms a bond together with the adjacent group R⁵;    R⁵ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group,    acyl, optionally substituted aralkyl or R⁵ forms a bond together    with R⁴; R⁶ may be hydrogen, optionally substituted groups selected    from alkyl cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl,    aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,    heterocyclyl, heteroaryl, heteroaralkyl groups, with a provision    that R⁶ does not represent hydrogen when R⁷ represents hydrogen or    lower alkyl group; R⁷ may be hydrogen or optionally substituted    groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,    heteroaryl, heteroaralkyl groups; Y represents oxygen or NR⁸, where    R⁸ represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl,    heterocyclyl, heteroaryl, heteroaralkyl groups; R⁷ and R⁸ together    may form a substituted or unsubstituted 5 or 6 membered cyclic    structure containing carbon atoms, which may optionally contain one    or more heteroatoms selected from oxygen, sulfur or nitrogen.

An example of these compounds is shown in formula (IIj)

-   ii) International publication No. WO 00/64888 disclose the compounds    of general formula (IIc)    wherein Ar¹ and Ar² are independently aryl, fused arylcycloalkenyl,    fused arylcycloalkyl, fused arylheterocyclenyl, fused    arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused    heteroarylcycloalkyl, fused heteroarylcyclenyl or fused    heteroarylheterocyclyl; A is O, S, SO, SO₂, NR¹³, C(O), NR¹⁴C(O),    C(O)NR¹⁴, NR¹⁴C(O)N(R¹⁵), C(R¹⁴)═N; chem bond and the like; B is O,    S, NR¹⁹, a chemical bond, C(O), N(R²⁰)C(O) or C(O)N(R²⁰); E is a    chemical bond or an ethylene group; a is 0-6; b is 0-4; c is 0-4; d    is 0-6; g is 1-5; h is 1-4; R¹, R³, R⁵ and R⁷ are independently    hydrogen, halogen, alkyl, carbonyl, alkoxycarbonyl, or aralkyl; R²,    R⁴, R⁶ and R⁸ are independently —(CH₂)_(q)—X; q is 0-3; X is    hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy,    heteroaralkoxy, carbonyl, alkoxycarbonyl, tetrazolyl, acyl,    acylHNSO₂, and the like; Z is R²¹O₂C, R²¹OC, cyclo-imide; CN,    R²¹O₂SHNCO, R²¹O₂SNH, R²¹NCO, R²¹O-2,4-thiazolidinonyl or    tetrazolyl.

An example of these compounds is shown in formula (IId)

-   iii) International publication Nos. WO 95/03038 and WO 96/04260    disclose compounds of formula (II e)    wherein R^(a) represents 2-benzoxazolyl or 2-pyridyl and R^(b)    represent CF₃, CH₂OCH₃ or CH₃. A typical example is    (S)-3-[4-[2-[N-2-benzoxazolyl)N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic    acid (II f).-   iv) International publication Nos. WO 94/13650, WO 94/01420 and WO    95/17394 disclose the compounds of general formula (II g)    A¹-X—(CH₂)_(n)—O-A²-A³-Y.R²  (II g)    wherein A¹ represent aromatic heterocycle, A² represents substituted    benzene ring and A³ represents moiety of formula (CH₂)_(m)—CH—(OR¹),    wherein R¹ represents alkyl groups, m is an integer of 1-5; X    represents substituted or unsubstituted N; Y represents C═O or C═S,    R² represents OR³ where R³ may be hydrogen, allyl, aralkyl, or aryl    group and n is an integer of 2-6.

An example of these compounds is shown in formula (II h)

-   v) International publication No. WO 00/49005 disclose the compounds    of general formula (II i)    wherein Het is an optionally substituted, saturated partially    saturated or fully unsaturated 8 to 10 membered bicyclic ring, R¹ is    optionally substituted aryl or optionally substituted heteroaryl, R²    is hydrogen halogen, lower alkyl or lower alkoxy, L¹ is an —R³-R⁴    linkage where R³ is alkylene, alkenylene or alkynylene and R⁴ is a    direct bond, cycloalkylene, heterocycloalkylene, arylene,    heteroarylidinyl, —C(=Z²)-NR⁵, NR⁵—C(=Z²), -Z²-, —C(═O), —C(═NOR⁵)—,    —NR⁵—, NR⁵—C(=Z²)—NR⁵, SO₂—NR⁵NR⁵—SO₂, —O—C(═O)—, —C(═O)—O,    —O—C(═O)—NR⁵, —NR⁵—C(═O)—O—; L² is optionally substituted alkylene    or alkenylene, Y is carboxy or an acid bioisostere and Z¹ is NR⁵ and    the corresponding N-oxides and their prodrugs and pharmaceutically    acceptable salts and solvates.

An example of these compounds is shown in formula (II j)

-   vi) International publication No. WO 94/12181 disclose the compounds    of general formula (II k)    X—Y-Z-Aryl-A-B  (II k)    aryl is a 6 membered aromatic ring containing 0, 1, 2 or 3 nitrogen    atoms and either unsubstituted or substituted with R⁸ and R⁹; X    represents NH₂, NH—C(═NH)—, and the like or 4 to 10 membered mono or    polycyclic aromatic or nonaromatic ring system and containing 0, 1,    2, 3 or 4 heteroatoms selected from N, O or S either unsubstituted    or substituted; Y is selected from C₀₋₈ alkyl, C₄₋₁₀ cycloalkyl,    C₀₋₈ alkyl-NR³—C₀₋₈ alkyl, C₀₋₈alkyl-CONR³—C₀₋₈ alkyl, C₀₋₈    alkyl-O—C₀₋₈ alkyl, C₀₋₈ alkyl-S(O)_(n)—C₀₋₈ alkyl, (CH₂)₀₋₈    aryl-(CH₂)₀₋₈, (CH₂)₀₋₆ aryl-SO_(n)—, (CH₂)₀₋₈ aryl-CO—(CH₂)₀₋₈,    (CH₂)₀₋₆ aryl-SO₂—(CH₂)₀₋₆, (CH₂)₀₋₆ NR³—(CH₂)₀₋₆, (CH₂)₀₋₆ aryl    CH(OH)—(CH₂)₀₋₆—, (CH₂)₀₋₈—CONH—(CH₂)₀₋₈—, C₀₋₈ alkyl-SO₂—NR³—C₀₋₈    alkyl, C₀₋₈ alkyl-CO—C₀₋₈ alkyl, C₀₋₈ alkyl-CH(OH)—C₀₋₈ alkyl, where    n is an integer from 0-2; Z and A are independently chosen from    (CH₂)_(m), (CH₂)_(m)O(CH₂)_(n), (CH₂)_(m)NR³(CH₂)_(n),    (CH₂)_(m)NR³(CH₂)_(n), (CH₂)_(m)CONR¹¹(CH₂)_(n),    (CH₂)_(m)CO(CH₂)_(n), (CH₂)_(m)CS(CH₂)_(n), (CH₂)_(m)SO₂(CH₂)_(n),    (CH₂)_(m)S(CH₂)_(n), (CH₂)_(m)SO₂(CH₂)_(n), (CH₂)_(m)SO(CH₂)_(n),    (CH₂)_(m)SO₂NR³(CH₂)_(n), (CH₂)_(m)NR³SO₂(CH₂)_(m)CR³═CR⁴(CH₂)_(n),    (CH₂)_(m)C≡C(CH₂)_(n), (CH₂)_(m)CH(OH)(CH₂)_(n); where m and n are    each independently an integer from 0 to 6; Aryl is a 6 membered    aromatic ring system containing 0, 1, 2, 3 or 4 N atoms and either    unsubstituted or substituted with R⁵, provided that when A is    (CH₂)_(n), the Aryl ring, bonded by Z and A must contain at least    one heteroatom;-   B is-   R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹, are independently selected from    hydrogen, fluorine, (C₁₋₈) alkyl, hydroxy, hydroxy(C₁₋₆)alkyl,    carboxy(C₀₋₆)alkyl, (C₁₋₆)alkyloxy, aryl(C₀₋₆)alkyloxy,    (C₃₋₈)cycloalkyl, aryl(C₀₋₆)alkyl, (C₁₋₆)alkylcarbonyloxy,    (C₀₋₆)alkylamino(C₀₋₆)alkyl and the like; R¹² is selected from    hydroxy, (C₁₋₈)alkyloxy, aryl(C₀₋₆)alkyl and the like;

An example of these compounds is shown in formula (II l)

-   vii) International publication No. WO 93/16697 and U.S. Pat. No.    5,227,490 disclose the compounds of general formula (II m)    R¹ is chosen from hydrogen, C₁₋₆ alkyl, aryl C₄₋₁₀ alkyl, aryl,    carboxy, C₁₋₆ alkyloxy, carboxy C₀₋₆ alkyl, carboxy C₁₋₆ alkyloxy,    hydroxy C₀₋₆ alkyl, C₁₋₄ alkylsulfonyl C₀₋₆ alkyl, C₀₋₄ alkylamino    C₀₋₆ alkyl, aryl C₀₋₁₀ alkylamino C₀₋₆ alkyl, C₂₋₁₀ acylamino C₀₋₆    alkyl, C₁₋₄ carboalkoxy C₀₋₆ alkyl halogen, R² is independently    chosen from hydrogen, halogen, hydroxy, C₁₋₆ alkyl, wherein the    alkyl group is substituted or unsubstituted, C₁₋₆alkyloxy, aryl C₀₋₄    alkyl, aryl C₀₋₆ alkyloxy and the like; R³ hydrogen, C₀₋₆ alkyl,    aryl C₁₋₁₀ alkyl; Z is NR⁴R⁵ or a 4-9 membered mono or bicyclic ring    system containing 1, 2 or 3 heteroatoms selected from N, O or S and    either unsubstituted or substituted; Y is C₁₋₆ alkyl either    unsubstituted or substituted, C₄₋₈ cycloalkyl, aryl, —C(═O)NH—,    —NH(C═O)— and the like; X is O, SO, SO₂, S, CO, —NReCO—, CONR⁴—, CH₂    and the like;

An example of these compounds is shown in formula (II n)

SUMMARY OF THE INVENTION

With an objective to develop novel compounds for reducing blood glucose,lipid levels, lowering cholesterol and reducing body weight withbeneficial effects in the treatment and/or prophylaxis of diseasesrelated to increased levels of lipids, atherosclerosis, coronary arterydiseases, Syndrome-X, impaired glucose tolerance, insulin resistance,insulin resistance leading to type 2 diabetes and diabetic complicationsthereof, for the treatment of diseases wherein insulin resistance is thepathophysiological mechanism and for the treatment of hypertension, withbetter efficacy, potency and lower toxicity, we focused our research todevelop new compounds effective in the treatment of the above mentioneddiseases. Effort in this direction has led to compounds having generalformula (I).

The main objective of the present invention is therefore, to providenovel alkyl carboxylic acids, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates and pharmaceutical compositions containing them, or theirmixtures.

Another objective of the present invention is to provide novel alkylcarboxylic acids, their derivatives, their analogs, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts, their pharmaceutically acceptable solvates andpharmaceutical compositions containing them or their mixtures which mayhave agonist activity against PPARα and/or PPARγ, and optionally inhibitHMG CoA reductase, in addition to having agonist activity against PPARαand/or PPARγ.

Another objective of the present invention is to provide novel alkylcarboxylic acids, their derivatives, their analogs, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts, their pharmaceutically acceptable solvates andpharmaceutical compositions containing them or their mixtures havingenhanced activities, without toxic effect or with reduced toxic effect.

Yet another objective of the present invention is to provide a processfor the preparation of alkyl carboxylic acids of formula (I), theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts and theirpharmaceutically acceptable solvates.

Still another objective of the present invention is to providepharmaceutical compositions containing compounds of the general formula(I), their analogs, their derivatives, their tautomers, theirstereoisomers, their polymorphs, their salts, solvates or their mixturesin combination with suitable carriers, solvents, diluents and othermedia normally employed in preparing such compositions.

Another objective of the present invention is to provide novelintermediates, a process for their preparation and use of theintermediates in processes for preparation of alkyl carboxylic acids offormula (I), their derivatives, their analogs, their tautomers, theirstereoisomers, their polymorphs, their salts and their pharmaceuticallyacceptable solvates and their use as antidiabetic, hypolipidemic,antiobesity and hypocholesterolemic compounds.

DETAILED DESCRIPTION OF THE INVENTION

Novel alkyl carboxylic acids of compound of the general formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, alkanoyl, acyl,substituted or unsubstituted aralkyl groups; R² represents hydrogen,hydroxy, halogen, substituted or unsubstituted groups selected fromalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanyl, alkanoyloxy,aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonylgroups; R³ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, eteroarylor heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ presentshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Grepresents O or S; X represents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, alkanoyloxy, aroyl, aralkanoyl,heterocyclyl, heteroaryl, heteroaralkyl groups or(C₁-C₁₂)alkylcarboxylic acid or its derivatives; Y represents O, S, NR⁶or CHR⁷; where R⁶ represents hydrogen or substituted or unsubstitutedgroups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; R⁷ represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R¹; m and p are integers ranging from 0-4; n is aninteger in the range of 1-4; A represents pyrazolopyrimidine orimidazolopyrimidine of the formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups, selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.

Suitable groups represented by R¹ may be selected from hydrogen,hydroxy, (C₁-C₆)alkyl groups such as methyl, ethyl, propyl and the like;(C₁-C₆)alkoxy such as methoxy, ethoxy, propoxy and the like; halogenatom such as fluorine, chlorine, bromine or iodine; (C₂-C₁₀)alkanoylgroup such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and thelike; aralkyl such as benzyl, phenethyl and the like, which may beunsubstituted or substituted or R¹ together with R⁷ forms a bond. Thesubstituents are selected from halogen, hydroxy or alkyl groups.

Suitable groups represented by R² may be selected from hydrogen,hydroxy, halogen atom such as chlorine, bromine, iodine or fluorine;linear or branched (C₁-C₁₆) alkyl, preferably (C₁-C₁₂)alkyl group suchas methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, pentyl, hexyl,heptyl, octyl and the like, the alkyl group may be substituted;(C₁-C₁₀)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy,iso-propyloxy, hexyloxy, octyloxy and the lice, which may besubstituted; (C₃-C₇)cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like, the cycloalkyl group may besubstituted; (C₃-C₇)cycloalkyl(C₁-C₁₀)alkyl group such ascyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl andthe like, which may be substituted; aryl group such as phenyl, naphthyland the like, the aryl group may be substituted; aralkyl group such asbenzyl, phenethyl and the like, the aralkyl group may be substituted;aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxygroup may be substituted; aralkoxy group such as benzyloxy,phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, thearalkoxy group may be substituted; heteroaryl group such as pyridyl,thienyl, pyrrolyl, furyl and the like, the heteroaryl group may besubstituted; heteroaralkyl group such as furanmethyl, pyridinemethyl,oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may besubstituted; heteroaryloxy and heteroaralkoxy, wherein heteroaryl andheteroaralkyl moieties are as defined earlier and may be substituted;heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and thelike, the heterocyclyl group may be substituted; linear or branched(C₂-C₁₆)alkanoyl group such as acetyl, propanoyl, butanoyl, benzoyl,octanoyl, decanoyl and the like, which may be substituted; alkanoyloxygroup such as OOCMe, OOCEt, OOCPh and the like which may be substituted;alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl,ethoxyethyl and the like, the alkoxyalkyl group may be substituted;(C₁-C₆)alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl andthe like, the alkoxycarbonyl group may be substituted; aryloxycarbonylsuch as phenoxycarbonyl, naphthyloxycarbonyl and the like, the arylgroup may be substituted; (C₁-C₆)alkylaminocarbonyl such asmethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and thelike, which may be substituted; arylaminocarbonyl such as PhNHCO,naphthylaminocarbonyl and the like, the aryl moiety may be substituted.The substituents may be selected from halogen, hydroxy, nitro orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl,heteroaryl, heteroaralkyl, alkanoyl, alkanoyloxy, hydroxyalkyl, amino,alkanoylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl,alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups,carboxylic acid or its derivatives or sulfonic acid or its derivatives.

Suitable groups represented by R³ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, pentyl, hexyl,heptyl, octyl and the like, the alkyl group may be substituted;(C₃-C₇)cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and thelike, the cycloalkyl group may be substituted; aryl group such asphenyl, naphthyl and the like, the aryl group may be substituted;heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like,the heteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; aralkyl group such asbenzyl, phenethyl and the like, the aralkyl group may be substituted;heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and thelike, the heterocyclyl group may be substituted. The substituents on R³may be selected from halogen, hydroxy, nitro or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl,alkanoyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, arylamino,aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl,alkylthio, thioalkyl groups, carboxylic acid or its derivatives such asamides, like CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂, CONHPh and the like,or esters such as COOCH₃, COOC₂H₅, COOC₃H₇ and the like, the carboxylicacid derivatives may be substituted; sulfonic acid or its derivativessuch as SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ and the like, or sulfonatessuch as mesylate, tosylate, triflate, OSO₂C₂H₅ and the like, thesulfonic acid derivatives may be substituted.

Suitable groups represented by R⁴, R⁵ and R⁶ may be selected fromhydrogen, substituted or unsubstituted linear or branched (C₁-C₁₆)alkyl,preferably (C₁-C₁₂)alkyl group such as methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, pentyl, hexyl, heptyl, octyl and the like;hydroxy(C₁-C₆)alkyl such as hydroxymethyl, hydroxyethyl, hydroxybutyland the like; aryl group such as phenyl, naphthyl and the like, the arylgroup may be substituted; aralkyl group such as benzyl, phenethyl,phenyl propyl, phenyl butyl, phenyl pentyl, phenyl hexyl, phenyl heptyland the like, the aralkyl group may be substituted; carboxyalkyl groupsuch as carboxymethyl, carboxyethyl, carboxypropyl and the like, whichmay be substituted; (C₂-C₆)alkanoyl group such as acetyl, propanoyl,butanoyl, pentanoyl, benzoyl and the like, which may be substituted;aralkanoyl group such as phenyl acetyl, naphthyl acetyl and the like,which may be substituted; aroyl such as benzoyl, substituted benzoyl andthe like; alkanoyloxy group such as OOCMe, OOCEt, OOCPh and the likewhich may be substituted; heterocyclyl group such as aziridinyl,pyrrolidinyl, piperidinyl and the like; heteroaryl group such aspyridyl, thienyl, pyrrolyl, furyl and the like; heteroaralkyl group suchas furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like;(C₁-C₁₂)alkylcarboxylic acid such as methyl carboxylic acid, ethylcarboxylic acid, propyl carboxylic acid, butyl carboxylic acid, hexycarboxylic acid, heptyl carboxylic acid and the like and theirderivatives such as esters or amides. The substituents may be selectedfrom halogen, hydroxy, nitro or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,aryloxy, aralkoxy, aralkoxyalkyl, heterocyclyl, heteroaryl,heteroaralkyl, hydroxyalkyl, amino, arylamino, aminoalkyl, alkylamino,alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives such as amides, like CONH₂, CONHMe, CONMe₂, CONHBEt, CONEt₂,CONHPh and the like, or esters such as COOCH₃, COOC₂H₅, COOC₃H₇ and thelike, the carboxylic acid derivatives may be substituted; sulfonic acidor its derivatives such as SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ and thelike, or sulfonates such as mesylate, tosylate, triflate, OSO₂C₂H₅ andthe like. The sulfonic acid derivatives may be substituted.

Suitable ring structures formed by R³ and R⁴ together may be selectedfrom pyrrolidinyl, piperidinyl morpholinyl, piperazinyl and the like.

Suitable groups represented by R⁷ may be selected from hydrogen,hydroxy, halogen atom such as fluorine, chlorine, bromine or iodine;lower alkyl groups such as methyl, ethyl, propyl and the like;(C₁-C₃)alkoxy such as methoxy, ethoxy, propoxy and the like; substitutedor unsubstituted aralkyl such as benzyl, phenethyl and the like or R⁷together with R¹ represents a bond. When the aralkyl group issubstituted, the substituents may be selected from hydroxy, halogenatom, nitro or amino groups.

Suitable groups represented by R⁸, R⁹ and R¹⁰ may be selected fromhydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine;hydroxy, cyano, nitro, formyl; substituted or unsubstituted(C₁-C₁₂)alkyl group, especially, linear or branched (C₁-C₁₀)alkyl group,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,n-pentyl, i-pentyl, hexyl, heptyl, octyl and the like; cyclo(C₃-C₆)alkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl and thelike, the cycloalkyl group may be substituted; (C₁-C₆)alkoxy such asmethoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, thealkoxy group may be substituted; cyclo(C₃-C₆)alkoxy group such ascyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and thelike, the cycloalkoxy group may be substituted; aryl group such asphenyl, naphthyl and the like, the aryl group may be substituted;aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxygroup may be substituted; aralkyl such as benzyl, phenethyl,C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, the aralkyl group may besubstituted; aralkoxy group such as benzyloxy, phenethyloxy,naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group maybe substituted; heterocyclyl groups such as aziridinyl, pyrrolidinylmorpholinyl piperidinyl, piperazinyl and the like, the heterocyclylgroup may be substituted; heteroaryl group such as pyridyl, thienyl,furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroarylgroup may be substituted; heteroaralkyl group such as furanmethyl,pyridinemethyl oxazolemethyl, oxazolethyl and the like, theheteroaralkyl group may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are asdefined earlier and may be substituted; alkanoyl group such as acetyl,propanoyl and the like, the alkanoyl group may be substituted; aroylsuch as benzoyl substituted benzoyl and the like; alkanoyloxy group suchas OOCMe, OOCEt, OOCPh and the like which may be substituted;hydroxy(C₁-C₆)alkyl, which may be substituted; amino; alkanoylaminogroups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇, NHCOC₆H₅, which may besubstituted; mono(C₁-C₆)alkylamino group such as NHCH₃, NHC₂H₅, NHC₃H₇,NHC₆H₁₃ and the like, which may be substituted; (C₁-C₆)dialkylaminogroup such as N(CH₃)₂, NCH₃(C₂H₅) and the like, which may besubstituted; arylamino group such as HNC₆H₅, NCH₃(C₆H₅), NHC₆H₄CH₃,NHC₆H₄-Hal and the like, which may be substituted; aralkylamino groupsuch as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH₃ and the like, which may besubstituted; amino(C₁-C₆)alkyl, which may be substituted; alkoxycarbonylsuch as methoxycarbonyl, ethoxycarbonyl and the like, which may besubstituted; aryloxycarbonyl group such as phenoxycarbonyl,naphthyloxycarbonyl and the like, which may be substituted;aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl,naphthylmethoxycarbonyl and the like, which may be substituted;alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl,ethoxyethyl and the like, the alkoxyalkyl groups may be substituted;aryloxyalkyl group such as C₆H₅OCH₂, C₆H₅OCH₂CH₂, naphthyloxymethyl andthe like, which may be substituted; aralkoxyalkyl group such asC₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like, which may be substituted;thio(C₁-C₆)alkyl such as thiomethyl, thioethyl and the like, which maybe substituted; (C₁-C₆)alkylthio such as methylthio, ethylthio and thelike, which may be substituted; alkoxycarbonylamino group such asNHCOOC₂H₅, NHCOOCH₃ and the like, which may be substituted;aryloxycarbonylamino group such as NHCOOC₆H₅, N(CH₃)COOC₆H₅,N(C₂H₅)COOC₆H₅, NHCOOC₆H₄CH₃, NHCOOC₆H₄OCH₃ and the like, which may besubstituted; aralkoxycarbonylamino group such as NHCOOCH₂C₆H₅,NHCOOCH₂CH₂C₆H₅, N(CH₃)COOCH₂C₆H₅, N(C₂H₅)COOCH₂C₆H₅, NHCOOCH₂C₆H₄CH₃,NHCOOCH₂C₆H₄OCH₃ and the like, which may be substituted; carboxylic acidor its derivatives such as amides, like CONH₂, CONHMe, CONMe₂, CONHEt,CONEt₂, CONHPh and the like, or esters such as COOCH₃, COOC₂H₅, COOC₃H₇and the like, the carboxylic acid derivatives may be substituted;sulfonic acid or its derivatives such as SO₂NH₂, SO₂NHMe, SO₂NMe₂,SO₂NHCF₃, or sulfonates such as mesylate, tosylate, triflate, OSO₂C₂H₅and the like.

When the groups represented by R⁸, R⁹ and R¹⁰ are substituted, thesubstituent may be selected from halogen, hydroxy, nitro or substitutedor unsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, aralkoxyalkyl,heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, arylamino,aminoalkyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid or sulfonic acid.

Suitable groups represented by Ar may be selected from substituted orunsubstituted groups selected from divalent phenylene, naphthylene,pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl,benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl,azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Thesubstituents on the group represented by Ar may be selected from linearor branched optionally halogenated (C₁-C₆)alkyl, optionally halogenated(C₁-C₃)alkoxy, halogen, acyl, amino, acylamino, thio or carboxylic orsulfonic acids and their derivatives. The substituents are defined asthey are for R⁸-R¹⁰.

It is more preferred that Ar represent substituted or unsubstituteddivalent, phenylene, naphthylene, benzofuryl, pyrrolyl, indolyl,indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl orbenzoxazolyl groups.

Suitable n is an integer ranging from 1-4.

Suitable m and p are integers ranging from 04.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, Al, Mn; salts of organic bases such as N,N′-diacetylethylenediamine,betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine,piperidine, procaine, theobromine, glycinol, diethylamine,triethylamine, trimethylamine, tripropylamine, tromethamine, adamentylamine, diethanolamine, meglumine, ethylenediamine,N,N′-diphenylethylenediamine, N,N′-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine,metformin, benzylamine, phenylethylamine, thiamine, aminopyrimidine,aminopyridine, purine, spermidine, and the like; chiral bases likealkylphenylamine, phenyl glycinol and the like, salts of natural aminoacids such as glycine, alanine, valine, leucine, isoleucine, norleucine,tyrosine, cystine, cysteine, methionine, proline, hydroxy proline,histidine, ornithine, lysine, arginine, serine, threonine,phenylalanine; unnatural amino acids such as D-isomers or substitutedamino acids; guanidine, substituted guanidine wherein the substituentsare selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium orsubstituted ammonium salts. Salts may include acid addition salts whereappropriate which are, sulphates, nitrates, phosphates, perchlorates,borates, hydrohalides, acetates, tartrates, maleates, citrates,succinates, palmoates, methanesulfonates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates and the like. Pharmaceutically acceptable solvates may behydrates or comprising other solvents of crystallization such asalcohols.

Particularly useful compounds according to the present inventioninclude:

-   Ethyl    2-[4-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl(heptyl)carboxamido)phenylsulfanyl]pentanoate    or its salts in its single enantiomeric form or as a racemate;-   2-[4-5-Ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl-(heptyl)carboxamido)phenylsulfanyl]pentanoic    acid or its salts in its single enantiomeric form or as a racemate;-   Ethyl    2-ethoxy-3-[4-{2-(5-ethyl-1-methyl-3-propyl-1H-pyrazol[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoate    or its salts in its single enantiomeric form or as a racemate;-   Methyl    2-ethoxy-3-[4-{2-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-7-yloxy)ethoxy}phenyl]propanoate    or its salts in its single enantiomeric form or as a racemate;-   2-Ethoxy-3-[4-{2-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoic    acid or its salts in its single enantiomeric form or as a racemate;-   Ethyl    3-[4-{2-(1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoate    or its salts in its single enantiomeric form or as a racemate;-   3-[4-{2-(1,5-Dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)-ethoxy}phenyl]ethoxypropanoic    acid or its salts in its single enantiomeric form or as a racemate;-   Ethyl    2-ethoxy-3-[4-{2-(1-methyl-5-phenyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoate    or its salts in its single enantiomeric form or as a racemate;-   3-[4-{2-(1-Methyl-5-phenyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoic    acid or its salts in its single enantiomeric form or as a racemate;-   Ethyl    3-[4-{2-(5-cyclopropyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]2-ethoxypropanoate    or its salts in its single enantiomeric form or as a racemate;-   3-[4-{2-5-Cyclopropyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoic    acid or its salts in its single enantiomeric form or as a racemate;-   Ethyl    6-[5-ethyl-1-methyl-3-propyl-1H-pyrrolo[4,3-d]pyrimidin-7-yloxy-methyl    {4-(1-ethyloxycarbonylbutoxyl)phenyl}carboxamido]hexanoate or its    salts in its single enantiomeric form or as a racemate;-   6-[4-(1-Carboxybutoxy)phenyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido]hexanoic    acid or its salts in its single enantiomeric form or as a racemate;-   Ethyl    3-[4-{1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl(4-fluorobenzyl)carboxamido}phenyl]-2-ethoxypropanoate    or its salts in its single enantiomeric form or as a racemate;-   3-[4-{1,5-Dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl(4-fluorobenzyl)carboxamido}phenyl]-2-ethoxypropanoic    acid or its salts in its single enantiomeric form or as a racemate;-   Ethyl    2-(4-[5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl    {4-(4-ethyloxycarbonylphenyl)butyl}carboxamido]phenoxy)pentanoate or    its salts in its single enantiomeric form or as a racemate;-   2-[4-{4-(4-Carboxyphenyl)butyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido}phenoxy]pentanoic    acid or its salts in its single enantiomeric form or as a racemate;

According to a feature of the present invention, the compounds ofgeneral formula (I) where Y represents CHR⁷ group, R⁷ and R¹ togetherrepresent a bond, G is O or S; Z represents oxygen atom; and all othersymbols are as defined earlier, can be prepared by any of the followingroutes shown in Scheme-I below.

Route 1: The reaction of a compound of the general formula (IIIa) whereall symbols are as defined earlier with a compound of formula (IIIb)where R¹¹ represents (C₁-C₆)alkyl, R represents substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl and all other symbols are as defined earlier to yieldcompound of general formula (I) where R² represents substituted orunsubstituted groups selected from alkoxy, aryloxy, aralkoxy,heteroaryloxy, heteroaralkoxy and all other symbols are as defined abovemay be carried out in the presence of a base such as alkali metalhydrides like NaH or KH; organolithiums such as LDA, TMEDA and the like;alkoxides such as NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixturesthereof. The reaction may be carried out in the presence of solventssuch as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.HMPA may be used as cosolvent. The reaction temperature may range from−78° C. to 50° C., preferably at a temperature in the range of −10° C.to 30° C. The reaction is more effective under anhydrous conditions. Thecompound of general formula (IIIb) may be prepared by Arbuzov reaction.

Alternatively, the compound of formula (I) may be prepared by reactingthe compound of formula (IIIa) where all symbols are as defined earlierwith Wittig reagents such as Hal⁻Ph₃P⁺CH—(OR)CO₂R³ under similarreaction conditions as described above.

Route 2: The compound of general formula (IIIc) where B representspyrazolopyrimidine or imidazolopyrimidine of the formula given below:

wherein Q represents O or S and all other symbols are as definedearlier, because of the keto-enol tautomersim, enol form reacts withcompound of general formula (IIId) where L¹ is a leaving group such ashalogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like; R¹ and R⁷ together represent abond and all other symbols are as defined earlier to produce compound offormula (I) where all symbols are as defined above. The reaction may becarried out in the presence of solvents such as DMSO, DMF, DME, THF,dioxane, ether and the like or mixtures thereof. The reaction may becarried out in an inert atmosphere that may be maintained by using inertgases such as N₂, argon, He and the like. The reaction may be effectedin the presence of a base such as alkalis like sodium hydroxide orpotassium hydroxide; alkali metal carbonates such as sodium carbonate orpotassium carbonate; alkali metal hydrides such as sodium hydride orpotassium hydride; organometallic bases like n-butyl lithium; alkalimetal amides like sodamide, organic base like triethyl amine or mixturesthereof. The amount of base may range from 1 to 5 equivalents, based onthe amount of the compound of formula (IIIc), preferably the amount ofbase ranges from 1 to 3 equivalents. Phase transfer catalysts such astetraalkylammonium halide or hydroxide may be added. Additives such asalkali metal halides such as LiBr may be added. The reaction may becarried out at a temperature in the range of 0° C.-150° C., preferablyat a temperature in the range of 15° C.-100° C. The duration of thereaction may range from 0.25 to 72 hours, preferably from 0.25 to 24hours.

Route 3: The reaction of a compound of the general formula (IIIa) whereall symbols are as defined earlier, with a compound of formula (IIIe)where R¹ represents hydrogen atom and all other symbols are as definedearlier may be carried out in the presence of a base. The nature of thebase is not critical. Any base normally employed for aldol condensationreaction may be employed; bases like metal hydride such as NaH, KH,metal alkoxides such as NaOMe, t-BuO⁻K⁺, NaOEt metal amides such asLiNH₂, LiN(ipr)₂ may be used. Aprotic solvents such as THF, ether,dioxane may be used. The reaction may be carried out in an inertatmosphere that may be maintained by using inert gases such as N₂, Ar,or He and the reaction is more effective under anhydrous conditions.Temperature in the range of −80° C. to 35° C. may be used. The β-hydroxyproduct initially produced may be dehydrated under conventionaldehydration conditions such as treating with p-TSA in solvents such asbenzene or toluene. The nature of solvent and dehydrating agent is notcritical. Temperature in the range of 20° C. to reflux temperature ofthe solvent used may be employed, preferably at reflux temperature ofthe solvent by continuous removal of water using a Dean-Stark waterseparator.

Route 4: The reaction of compound of formula (IIIg) where L¹ representsa leaving group such as halogen atom, p-toluenesulfonate,methanesulfonate, trifluoromethanesulfonate ard the like; and all othersymbols are as defined earlier with compound of formula (IIIf) where R¹and R⁷ together represent a bond and all other symbols are as definedearlier to produce a compound of the formula (I) defined above may becarried out in the presence of aprotic solvents such as THF, DMF, DMSO,DME and the like or mixtures thereof. The reaction may be carried out inan inert atmosphere that may be maintained by using inert gases such asN₂, Ar, He and the like. The reaction may be effected in the presence ofa base such as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof. Acetone may beused as solvent when Na₂CO₃ or K₂CO₃ is used as a base. The reactiontemperature may range from 0° C.-120° C., preferably at a temperature inthe range of 30° C.-100° C. The duration of the reaction may range from1 to 48 hours, preferably from 2 to 12 hours. The compound of formula(IIIf) can be prepared according to a known procedure by Wittig Homerreaction between the hydroxy protected aryl aldehyde such asbenzyloxyaryl aldehyde and compound of formula (IIIb), followed bydeprotection.

Route 5: The reaction of compound of general formula (IIIh) where A isas defined earlier and Hal represents halogen atom such as chlorine,bromine, fluorine or iodine, with compound of formula (IIIi) where R¹and R⁷ together represent a bond and all other symbols are as definedearlier to yield the compound of general formula (I) where all symbolsare as defined above may be carried out in the presence of a base suchas alkali metal hydrides like NaH or KH; organolithiums such as TMEDA,LDA and the like; alkoxides such as NaOMe, NaOEt, t-BuO⁻K⁺ and the likeor mixtures thereof. The reaction may be carried out in the presence ofsolvents such as THF, dioxane, DMF, DMSO, DME and the like or mixturesthereof. The reaction temperature may range from −78° C. to 120° C.,preferably at a temperature in the range of −10° C. to 80° C. Thereaction is more effective under anhydrous conditions.

Route 6: The reaction of compound of general formula (IIIj) where allsymbols are as defined earlier with a compound of general formula (EDwhere R¹ and R⁷ together represent a bond and all other symbols are asdefined earlier may be carried out using suitable coupling agents suchas EDCI, dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylatesuch as PPh₃/DEAD or DIAD and the like. The reaction may be carried outin the presence of solvents such as THF, DME, CH₂Cl₂, CHCl₃, toluene,acetonitrile, carbon tetrachloride and the like. The inert atmospheremay be maintained by using inert gases such as N₂, Ar, He and the like.The reaction may be effected in the presence of DMAP, HOBt and they maybe used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1equivalents. The reaction temperature may be in the range of −20° C. to100° C., preferably at a temperature in the range of 0° C. to 80° C. Theduration of the reaction may range from 0.5 to 24 hours, preferably from6 to 12 hours. The above condensation may also be made using mixedanhydride methodology.

Route 7: The reaction of a compound of formula (IIIk) where all symbolsare as defined earlier with a compound of formula (IIIl) where Rrepresents substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, heteroaryl or heteroaralkyl and where R³ is as definedearlier excluding hydrogen to yield compound of general formula (I)where R² represents substituted or unsubstituted groups selected fromalkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all othersymbols are as defined above may be carried out neat in the presence ofa base such as alkali metal hydrides like NaH, KH or organolithiums likeCH₃Li, BuLi, TMEDA, LDA and the like or alkoxides such as NaOMe, NaOEt,t-BuO⁻K⁺ and the like or mixtures thereof. The reaction may be carriedout in the presence of aprotic solvents such as THF, dioxane, DMF, DMSO,DME and the like or mixtures thereof. HMPA may be used as cosolvent. Thereaction temperature may range from −78° C. to 100° C., preferably at atemperature in the range of −10° C. to 50° C. The reaction is moreeffective under anhydrous condition.

Route 8: The compound of general formula (IIIc) where B representspyrazolopyrimidine or imidazolopyrimidine of the formula given below:

wherein Q represents O or S and all other symbols are as definedearlier, because of the keto-enol tautomersim, enol form reacts withcompound of general formula (IIIm) which represents compound of formula(IIIi) when G represents oxygen, R¹ and R⁷ together represent a bond andall other symbols are as defined earlier to produce compound of formula(I) where all symbols are as defined above. The reaction may be carriedout using suitable coupling agents such as EDCI, dicyclohexyl urea,triarylphosphine/dialkylazadicarboxylate such as PPh₃/DEAD or DIAD andthe like. The reaction may be carried out in the presence of solventssuch as THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, carbontetrachloride and the like. The inert atmosphere may be maintained byusing inert gases such as N₂, Ar, He and the like. The reaction may beeffected in the presence of DMAP, HOBt and they may be used in the rangeof 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents. The reactiontemperature may be in the range of −20° C. to 100° C., preferably at atemperature in the range of 0° C. to 80° C. The duration of the reactionmay range from 0.5 to 120 hours, preferably from 6 to 24 hours.

In yet another embodiment of the present invention, the compounds ofgeneral formula (I) where Y represent CHR⁷ group, wherein R⁷ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, substituted orunsubstituted aralkyl group; R¹ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, substituted or unsubstituted aralkylgroup; X, R², R³, n, Ar and A are as defined earlier, G is O or S and Zrepresents oxygen atom can be prepared by one or more of the processesshown in Scheme-II below:

Route 9: The reduction of compound of the formula (IVa) which representsa compound of formula (I) where R¹ and R⁷ together represent a bond andZ represents oxygen atom and all other symbols are as defined earlier,obtained as described earlier (Scheme-I), to yield a compound of thegeneral formula (I) where R¹ and R⁵ each represent hydrogen atom and allsymbols are as defined earlier, may be carried out in the presence ofgaseous hydrogen and a catalyst such as Pd(OH)₂/C, Pd/C, Rh/C, Pt/C,Ra—Ni, and the like. Mixtures of catalysts may be used. The reaction maybe conducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate, alcohol such as methanol, ethanol and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 5-100% w/w. The reaction may also be carried out byemploying metal solvent reduction such as magnesium in alcohol or sodiumamalgam in alcohol, preferably methanol. The reaction temperature mayrange from 20° C.-120° C., preferably at a temperature in the range of25° C.-100° C. The duration of the reaction may range from 1 to 48hours, preferably from 2 to 6 hours. The hydrogenation may be carriedout in the presence of metal catalysts containing chiral ligands toobtain a compound of formula (I) in optically active form. The metalcatalyst may contain Rhodium, Ruthenium, Indium and the like. The chiralligands may preferably be chiral phosphines such as optically pureenantiomers of 2,3-bis(diphenylphosphino)butane,1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane,2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane andthe like. Any suitable chiral catalyst may be employed which would giverequired optical purity of the product (I) (Ref: Principles ofAsymmetric Synthesis, Tetrahedron Series Vol 14, pp 311-316, Ed. BaldwinJ. E.).

Route 10: The reaction of compound of formula (IVb) where L¹ is aleaving group such as halogen atom, p-toluenesulfonate,methanesulfonate, trifluoromethanesulfonate and the like, R³ is asdefined earlier excluding hydrogen and all other symbols are as definedearlier with an alcohol of general formula (IVc), where R representssubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,heteroaryl or heteroaralkyl and all other symbols are as defined earlierto yield compound of general formula (I) where R² represents substitutedor unsubstituted groups selected from alkoxy, aryloxy, aralkoxy,heteroaryloxy, heteroaralkoxy and all symbols earlier may be carried outin the presence of solvents such as TNF, DMF, DMSO, DME and the like ormixtures thereof. The reaction may be carried out in an inert atmospherethat may be maintained by using inert gases such as N₂, Ar, He and thelike. The reaction may be effected in the presence of a base such asKOH, NaOH, NaOMe, NaOEt, t-BuO⁻K⁺ or NaH or mixtures thereof. Phasetransfer catalysts such as tetraalkyl ammonium halides or bisulphates orhydroxides may be employed. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-100° C.The duration of the reaction may range from 1 to 24 hours, preferablyfrom 2 to 6 hours.

Route 11: The reaction of compound of formula (IIIg) defined earlierwith compound of formula (IIIf) where all symbols are as defined earlierto produce a compound of the formula (I) defined above, may be carriedout in the presence of solvents such as THF, DMF, DMSO, DME and the likeor mixtures thereof. The reaction may be carried out in an inertatmosphere that is maintained by using inert gases such as N₂, Ar, Heand the like. The reaction may be effected in the presence of a basesuch as Na₂CO₃, K₂CO₃, NaH and the like or mixtures thereof. Acetone maybe used as a solvent when Na₂CO₃ or K₂CO₃ is used as a base. Thereaction temperature may range from 20° C.-120° C., preferably at atemperature in the range of 30° C.-80° C. The duration of the reactionmay range from 1 to 48 hours, preferably from 2 to 12 hours. Thecompound of formula (IIIf) may be prepared by using Wittig Homerreaction between the protected hydroxyaryl aldehyde and compound offormula (IIIb) followed by reduction of the double bond anddeprotection.

Route 12: The reaction of compound of general formula (IIIj) definedearlier with a compound of general formula (IIIf) where all symbols areas defined above may be carried out using suitable coupling agents suchas EDCI, dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylatesuch as PPh₃/DEAD or DIAD and the like. The reaction may be carried outin the presence of solvents such as THF, DME, CH₂Cl₂, CHCl₃, toluene,acetonitrile, carbon tetrachloride and the like. The inert atmospheremay be maintained by using inert gases such as N₂, Ar, He and the like.The reaction may be effected in the presence of DMAP, HOBt and they maybe used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1equivalents. The reaction temperature may be in the range of −20° C. to100° C., preferably at a temperature in the range of 0° C. to 80° C. Theduration of the reaction may range from 0.5 to 24 hours, preferably from6 to 12 hours. The above condensation may also be made using mixedanhydride methodology.

Route 13: The reaction of compound of formula (IVd), which represents acompound of formula (I), when R² represents hydroxy group and all othersymbols are as defined above with a compound of formula (IVe) where Rrepresents substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, heteroaryl or heteroaralkyl and L² is a halogen atom toyield compound of general formula (I) where R² represents substituted orunsubstituted groups selected from alkoxy, aryloxy, aralkoxy,heteroaryloxy, heteroaralkoxy and all symbols are as defined earlier maybe carried out in the presence of solvents such as THF, DMF, DMSO, DMEand the like. The inert atmosphere may be maintained by using inertgases such as N₂, Ar, He and the like. The reaction may be effected inthe presence of a base such as KOH, NaOH, NaOMe, t-BuO⁻K⁺, NaH, KH andthe like. Phase transfer catalyst such as tetraalkyl ammonium halides orbisulphates or hydroxides may be employed. The reaction temperature mayrange from 20° C. to 150° C., preferably at a temperature in the rangeof 25° C. to 100° C. The duration of the reaction may range from 1 to 24hours, preferably from 2 to 6 hours.

Route 14: The reaction of compound of general formula (IIIh) where Halrepresents halogen atom and A is as defined earlier with the compound offormula (IIIi) where all other symbols are as defined earlier to yieldthe compound of general formula (I) where all symbols are as definedabove may be carried out in the presence of a base such as alkali metalhydrides like NaH or KH; organolithiums such as TMEDA, LDA and the like;alkoxides such as NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixturesthereof. The reaction may be carried out in the presence of solventssuch as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.The reaction temperature may range from −78° C. to 120° C., preferablyat a temperature in the range of −10° C. to 80° C. The reaction is moreeffective under anhydrous conditions.

Route 15: The compound of general formula (IIIc) where B representspyrazolopyrimidine or imidazolopyrimidine of the formula given below:

wherein Q represents O or S and all other symbols are as definedearlier, because of the keto-enol tautomersim, enol form reacts withreacts with compound of general formula (IIIm) which represents compoundof formula (IIIi) when G is oxygen and all other symbols are as definedearlier to produce compound of formula (I) where all symbols are asdefined above. The reaction may be carried out using suitable couplingagents such as EDCI, dicyclohexyl urea,triarylphosphine/dialkylazadicarboxylate such as PPh₃/DEAD or DIAD andthe like. The reaction may be carried out in the presence of solventssuch as THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, carbontetrachloride and the like. The inert atmosphere may be maintained byusing inert gases such as N₂, Ar, He and the like. The reaction may beeffected in the presence of DMAP, HOBt and they may be used in the rangeof 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents. The reactiontemperature may be in the range of 0° C. to 100° C., preferably at atemperature in the range of 20° C. to 80° C. The duration of thereaction may range from 0.5 to 120 hours, preferably from 6 to 24 hours.

Route 16: The reaction of a compound of the general formula (IIIa) asdefined above with a compound of formula (IIIe) where R¹ representshydrogen atom and all other symbols are as defined earlier may becarried out in the presence of base. The base is not critical. Any basenormally employed for aldol condensation reaction may be employed, metalhydride such as NaH or KH; metal alkoxides such as NaOMe, t-BuO⁻K^(t) orNaOEt; metal amides such as LiNH₂, LiN(iPr)₂. Aprotic solvent such asTHF may be used. Inert atmosphere may be employed such as N₂ or argon orHe and the reaction is more effective under anhydrous conditions.Temperature in the range of −80° C. to 25° C. may be used. The β-hydroxyaldol product may be dehydroxylated using conventional methods,conveniently by ionic hydrogenation technique such as by treating with atrialkyl silane in the presence of an acid such as trifluoroacetic acid.Solvent such as CH₂Cl₂ may be used. Favorably, reaction proceeds at 25°C. Higher temperature may be employed if the reaction is slow.

Route 17: The compound of general formula (IIIc) where B representspyrazolopyrimidine or imidazolopyrimidine of the formula given below:

wherein Q represents O or S and all other symbols are as definedearlier, because of the keto-enol tautomersim, enol form reacts withreacts with compound of general formula (IIId) where L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like; all other symbols are as definedearlier to produce compound of formula (I) where all symbols are asdefined above. The reaction may be carried out in the presence ofsolvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or acombination thereof. The reaction may be carried out in an inertatmosphere that may be maintained by using inert gases such as N₂, Ar,He and the like. The reaction may be effected in the presence of a basesuch as alkalis like sodium hydroxide, potassium hydroxide; alkali metalcarbonates like sodium carbonate or potassium carbonate; alkali metalhydrides such as sodium hydride or potassium hydride; organometallicbases like LDA, TMEDA; alkali metal amides like sodamide or mixturesthereof. The amount of base may range from 1 to 5 equivalents, based onthe amount of the compound of formula (IIIc), preferably the amount ofbase ranges from 1 to 3 equivalents. Additives such as alkali metalhalides such as LiBr may be added. The reaction may be carried out at atemperature in the range of 0° C. to 150° C., preferably at atemperature in the range of 15° C. to 100° C. The duration of thereaction may range from 0.25 to 48 hours, preferably from 0.25 to 24hours.

Route 18: The conversion of compound of formula (IVf) where all symbolsare as defined earlier to a compound of formula (I) may be carried outeither in the presence of base or acid and the selection of base or acidis not critical. Any base normally used for hydrolysis of nitrile toacid may be employed, metal hydroxides such as NaOH or KOH in an aqueoussolvent or any acid normally used for hydrolysis of nitrile to ester maybe employed such as HCl in an excess of alcohol such as methanol,ethanol, propanol etc. The reaction may be carried out at a temperaturein the range of 0° C. to reflux temperature of the solvent used,preferably at a temperature in the range of 25° C. to reflux temperatureof the solvent used. The duration of the reaction may range from 0.25 to48 hrs.

Route 19: The reaction of a compound of formula (IVg) where R³ is asdefined earlier excluding hydrogen and all other symbols are as definedearlier with a compound of formula (IVc) where R represents substitutedor unsubstituted groups selected from alkyl, aryl, aralkyl, heteroarylor heteroaralkyl and L² is a halogen atom to yield compound of generalformula (I) where R² represents substituted or unsubstituted groupsselected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxyand all other symbols are as defined earlier (by a rhodium carbenoidmediated insertion reaction) may be carried out in the presence ofrhodium (II) salts such as rhodium (II) acetate. The reaction may becarried out in the presence of solvents such as benzene, toluene,dioxane, ether, THF and the like or a combination thereof or whenpracticable in the presence of ROH as solvent at any temperatureproviding a convenient rate of formation of the required product,generally at an elevated temperature, such as reflux temperature of thesolvent. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar, He and the like. The duration of the reaction may rangefrom 0.5 to 24 h, preferably from 0.5 to 6 h.

In yet another embodiment of the present invention the compound ofgeneral formula (I) where Y represents O or S or NR⁶ group where R⁶represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Xrepresents NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—,—(CH₂)_(p)NR⁵CO— where m and p are as defined earlier; G is O or S and Zrepresents oxygen atom; R¹, R², R³, A, n and Ar are as defined earlier,can be prepared by any of the following routes shown in Scheme-IIIbelow.

Route 20: The reaction of compound of formula (Va) where all symbols areas defined earlier with compound of formula (Vb) where L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like, and all other symbols are asdefined earlier to produce a compound of the formula (I) defined abovemay be carried out in the presence of aprotic solvents such as THF, DMF,DMSO, DME and the like; organic base like triethyl amine, lutidine,collidine and the like or mixtures thereof. The reaction may be carriedout in an inert atmosphere that may be maintained by using inert gasessuch as N₂, Ar, He and the like. The reaction may be effected in thepresence of a base such as K₂CO₃, Na₂CO₃, NaH, KH and the like ormixtures thereof. Acetone may be used as solvent when Na₂CO₃ or K₂CO₃ isused as a base. The reaction temperature may range from 0° C.-120° C.,preferably at a temperature in the range of 25° C.-100° C. The durationof the reaction may range from 1 to 96 hours, preferably from 2 to 24hours.

Route 21: The reaction of a compound of general formula (IIIc) where Brepresents pyrazolopyrimidine or imidazolopyrimidine of the formulagiven below:

wherein Q represents O or S and all other symbols are as definedearlier, because of the keto-enol tautomerism, enol form reacts withreacts with compound of general formula (IIId) where L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like, and all other symbols are asdefined earlier to produce a compound of general formula (I) where allsymbols are as defined above may be carried out in the presence ofsolvents such as DMSO, DMF, DME, THF, dioxane, ether, acetone and thelike or mixtures thereof. The reaction may be carried out in an inertatmosphere that may be maintained by using inert gases such as N₂,argon, He and the like. The reaction may be effected in the presence ofa base such as alkalis like sodium hydroxide or potassium hydroxide;alkali metal carbonates such as sodium carbonate or potassium carbonate;alkali metal hydrides such as sodium hydride or potassium hydride;organometallic bases like n-BuLi, TMEDA(N,N,N′,N′-tetramethylethylenediamine), LDA; alkali metal amides likesodamide, organic base like triethyl amine, lutidine, collidine ormixtures thereof. The amount of base may range from 1 to 5 equivalents,based on the amount of the compound of formula (IIIc), preferably theamount of base ranges from 1 to 3 equivalents. Phase transfer catalystssuch as tetraalkylammonium halide or sulphonates or hydroxide may beadded. Additives such as alkali metal halides like LiBr may be added.The reaction may be carried out at a temperature in the range of 0°C.-150° C., preferably at a temperature in the range of 15° C.-100° C.The duration of the reaction may range from 0.25 to 72 hours, preferablyfrom 0.25 to 24 hours.

Route 22: The reaction of compound of formula (Vc) where L¹ represents aleaving group such as halogen atom, p-toluenesulfonate,methanesulfonate, trifluoromethanesulfonate and the like, and all othersymbols are as defined earlier with compound of formula (IIIf) where allsymbols are as defined earlier to produce a compound of the formula (I)defined above may be carried out in the presence of aprotic solventssuch as THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere that may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be effected in the presence of a base such as K₂CO₃, Na₂CO₃or NaH, KH, triethyl amine and the like or mixtures thereof. Acetone maybe used as solvent when Na₂CO₃ or K₂CO₃ is used as a base. The reactiontemperature may range from 0° C.-120° C., preferably at a temperature inthe range of 25° C.-100° C. The duration of the reaction may range from1 to 72 hours, preferably from 2 to 24 hours.

Route 23: The reaction of compound of general formula (IIIh) where A isas defined earlier and Hal represents halogen atom with the compound offormula (IIIi) where all symbols are as defined earlier to yieldcompound of general formula (I) where all symbols are as defined abovemay be carried out in the presence of a base such as alkali metalhydrides like NaH or KH; organolithiums such as TMEDA, LDA and the like;alkoxides such as NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixturesthereof. The reaction may be carried out in the presence of solventssuch as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.The reaction temperature may range from −78° C. to 120° C., preferablyat a temperature in the range of −10° C. to 80° C. The reaction is moreeffective under anhydrous conditions.

Route 24: The reaction of compound of formula (Vd) where all symbols areas defined earlier with a compound of general formula (IIIf) where allsymbols are as defined earlier may be carried out using pivaloylchloride, ethyl chloroformate, isobutyl chloroformate and the like. Thereaction may be carried out in the presence of solvents such as CH₂Cl₂,DMF, THF and the like or mixtures thereof. The inert atmosphere may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be carried out in the presence of bases like triethylamine, lutidine, collidine and the like. The reaction temperature may bein the range of −20° C. to 80° C., preferably at a temperature in therange of 0° C. to 50° C. The duration of the reaction may range from 0.5to 24 hours, preferably from 0.5 to 12 hours.

This reaction can also be carried out by a method described in Route 25.

Route 25: The reaction of compound of general formula (IIIc) where Brepresents pyrazolopyrimidine or imidazolopyrimidine of the formulagiven below:

wherein Q represents O or S and all other symbols are as definedearlier, because of the keto-enol tautomerism, enol form reacts withreacts with compound of general formula (IIIm) where all symbols are asdefined earlier to afford compound of general formula (I) where allsymbols are as defined earlier may be carried out using suitablecoupling agents such as EDCI(N-ethyl-N′-3-dimethylaminopropyl)carbodimide hydrochloride),dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such asPPh₃/DEAD or DIAD and the like. The reaction may be carried out in thepresence of solvents such as THF, DME, CH₂Cl₂, CHCl₃, toluene,acetonitrile, carbon tetrachloride and the like. The inert atmospheremay be maintained by using inert gases such as N₂, Ar, He and the like.The reaction may be effected in the presence of DMAP, HOBt and they maybe used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1equivalents. The reaction temperature may be in the range of −20° C. to100° C., preferably at a temperature in the range of 0° C. to 80° C. Theduration of the reaction may range from 0.5 to 48 hours, preferably from6 to 18 hours.

Route 26: The conversion of compound of formula (IVf) where all symbolsare as defined earlier to a compound of formula (I) may be carried outeither in the presence of base or acid and the selection of base or acidis not critical. Any base normally used for hydrolysis of nitrile toacid may be employed, metal hydroxides such as NaOH or KOH in an aqueoussolvent or any acid normally used for hydrolysis of nitrile to ester maybe employed such as HCl in an excess of alcohol such as methanol,ethanol, propanol etc. The reaction may be carried out at a temperaturein the range of 0° C. to reflux temperature of the solvent used,preferably at a temperature in the range of 25° C. to reflux temperatureof the solvent used. The duration of the reaction may range from 0.25 to48 hrs.

Route 27: The reaction of compound of general formula (IIIj) where A, Gand n are as defined earlier with a compound of general formula (IIIf)where all symbols are as defined earlier may be carried out usingsuitable coupling agents such as EDCI, dicyclohexyl urea,triarylphosphine/dialkylazadicarboxylate such as PPh₃/DEAD or DIAD andthe like. The reaction may be carried out in the presence of solventssuch as THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, carbontetrachloride and the like. The inert atmosphere may be maintained byusing inert gases such as N₂, Ar, He and the like. The reaction may beeffected in the presence of DMAP, HOBt and they may be used in the rangeof 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents. The reactiontemperature may be in the range of −20° C. to 100° C., preferably at atemperature in the range of 0° C. to 80° C. The duration of the reactionmay range from 0.5 to 48 hours, preferably from 6 to 18 hours. The abovecondensation may also be made using mixed anhydride methodology asdescribed in Route 24.

The compound of formula (I) where R³ represents hydrogen atom may beprepared by hydrolysing, using conventional methods, a compound offormula (I) where R³ represents all groups defined earlier excludinghydrogen. The hydrolysis may be carried out in the presence of a basesuch as Na₂CO₃, K₂CO₃, NaOH, KOH, LiOH and the like and a suitablesolvent such as methanol, ethanol, dioxane, water and the like ormixtures thereof THF is used as solubilizing agent wherever necessary.The reaction may be carried out at a temperature in the range of 20° C.to reflux temperature of the solvent, preferably at 25° C. to refluxtemperature. The reaction time may range from 1 to 48 h, preferably from1 to 12 h.

The compound of general formula (I) where Z represents oxygen and R³represents hydrogen or lower alkyl group may be converted to compound offormula (I), where Z represents NR⁴ by reaction with appropriate aminesof the formula NHR³R⁴, where R³ and R⁴ are as defined earlier to yield acompound of formula (I) where Z represents NR⁴ and all other symbols areas defined earlier. Alternatively, the compound of formula (I) where ZR³represents OH may be converted to acid halide, preferably ZR³═Cl byreacting with appropriate reagents such as oxalyl chloride, thionylchloride and the like, followed by treatment with amines of the formulaNHR³R⁴ where R³ and R⁴ are as defined earlier. Alternatively, mixedanhydrides may be prepared from compound of formula (I) where ZR³represents OH and all other symbols are as defined earlier by treatingwith acid halides such acetyl chloride, acetyl bromide, pivaloylchloride, dichlorobenzoyl chloride and the like. The reaction may becarried out in the presence of pyridine, triethylamine, diisopropylethylamine and the like. Coupling reagents such as DCC/DMAP, DCC/HOBt,EDCI/HOBt, ethylchloroformate, isobutylchloroformate can also be used toactivate the acid. Solvents such as halogenated hydrocarbons like CHCl₃or CH₂Cl₂; hydrocarbons such as benzene, toluene, xylene and the likemay be used. The reaction may be carried out at a temperature in therange of −40° C. to 40° C., preferably at a temperature in the range of0° C. to room temperature. The acid halide or mixed anhydride oractivated acid obtained by coupling reagents described above thusprepared may further be treated with appropriate amines of the formulaNHR³R⁴ where R³ and R⁴ are as defined earlier to yield a compound offormula (I) where Z represents NR⁴ and all other symbols are as definedearlier.

In still another embodiment of the present invention the novelintermediate of formula (IIIf)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; R³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—,—(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl,heteroaralkyl groups or (C₁-C₁₂)alkylcarboxylic acid and itsderivatives; Y represents O, S, NR⁶ or CHR⁷; where R⁶ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷ represents hydrogenatom, halogen, hydroxy, alkyl, alkoxy, substituted or unsubstitutedaralkyl group or forms a bond together with the adjacent group R¹; m andp are integers ranging from 0-4 is provided.

In yet another embodiment of the present invention, the compound offormula (IIIf) where X represents NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)NR⁵CO—, where p is 0, m is 0-4, R⁵ is as defined above; Yrepresents O, S, NR⁶ or CHR⁷ all other symbols are as defined above maybe prepared by any of the following the processes described in scheme-IVbelow:

Route 28: The reduction of compound of the formula (IIIf-1) where allsymbols are as defined above to yield compound of the general formula(IIIf) where R⁵ represents hydrogen; and all other symbols are asdefined above may be carried out in the presence of gaseous hydrogen anda catalyst such as Pd/C, Rh/C, Pt/C, and the like. Mixtures of catalystsmay be used. The reaction may also be carried out in the presence ofsolvents such as dioxane, acetic acid, ethyl acetate, alcohol such asmethanol, ethanol and the like or mixture thereof. A pressure betweenatmospheric pressure and 40 to 80 psi may be employed. The catalyst maybe preferably 5-10% Pd/C and the amount of catalyst used may range from5-100% w/w. The reaction may also be carried out by employing metalsolvent reduction such as magnesium or samarium in alcohol or sodiumamalgam in alcohol, preferably methanol. When R¹ and R² represent doublebond, the hydrogenation may be carried out in the presence of metalcatalysts containing chiral ligands to obtain a compound of formula(IIIf) in optically active form. The metal catalyst may contain Rhodium,Ruthenium, Indium and the like. The chiral ligands may preferably bechiral phosphines such as optically pure enantiomers of2,3-bis(diphenylphosphino)butane,2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane andthe like. Any suitable chiral catalyst may be employed which would giverequired optical purity of the product (I) (Ref: Principles ofAsymmetric Synthesis, Tetrahedron Series Vol 14, pp 311-316, Ed. BaldwinJ. E.).

Route 29: The reaction of compound of formula (IIIf-2) with compound offormula (IIIf-3) to give a compound of formula (IIIf) where R⁵represents alkyl group and all other symbols are as defined above may becarried out in two steps the first step being the imine formation,followed by reduction. Formation of imine may be carried out in solventssuch as MeOH, EtOH, i-PrOH and the like. The reaction may be effected inthe presence of a promoter such as NaOAc, KOAc and the like or themixtures thereof. The temperature of reaction may range from roomtemperature to the reflux temperature of the solvent used. The reactiontime may be 2 h to 24 h, preferably in the range 2 h to 12 h.

The imine can also be obtained by the reaction of a compound of generalformula (IIIf-2) with a compound of formula (IIIf-3) using solvents suchas CH₂Cl₂, CHCl₃, chlorobenzene, benzene, THF, in the presence ofcatalyst such as p-toluenesulfonic acid, methanesulfonic acid, TFA,TfOH, BF₃—OEt₂ and the like. The reaction may also be carried out inpresence of activated molecular sieves. The temperature of the reactionmay range from 10° C. to 100° C., preferably at a temperature in therange from 10° C. to 60° C. The reaction time may be 1 h to 48 h.

The imine product thus obtained above may be reduced by usingNa(CN)BH₃—HCl (ref: Hutchins, R. O. et al. J. Org. Chem. 1983, 48,3433), NaBH₁, H₂—Pd]/C, H₂—t/C; H₂—Rh/C and the like in solvents such asmethanol, ethanol and the like.

Route 30: The conversion of compound of formula (IIIf-4) to a compoundof formula (IIIf) where R⁵ represents hydrogen, and all other symbolsare as defined above may be carried out in two steps the first stepbeing the imine formation, followed by reduction. Formation of imine maybe carried out in solvents such as MeOH, EtOH, i-PrOH and the like usinghydroxylamine hydrochloride. The reaction may be effected in thepresence of a promoter such as NaOAc, KOAc and the like or the mixturesthereof. The temperature of reaction may range from room temperature tothe reflux temperature of the solvent used. The reaction time may be 2 hto 24 h, preferably in the range 2 h to 12 h.

The imine product thus obtained above may be reduced by usingNa(CN)BH₃—HCl (ref: Hutchins, R. O. et al. J. Org Chem. 1983, 48, 3433),NaBH₄, H₂—Pd]/C, H₂—Pt/C, H₂—Rh/C and the like in solvents such asmethanol, ethanol and the like.

Alternatively, the conversion of compound of formula (IIIf-4) to acompound of formula (IIIf) where R⁵ represents hydrogen, and all othersymbols are as defined above may be carried out using TiCl₃ as reagentand a reducing agent such as NaCNBH₃, or Na₂BH₄. The coactivators likeammonium acetate can be used. The reaction may be carried out in thepresence of solvents such as methanol, ethanol water and the like. Thetemperature of reaction may range from −20° C. to the reflux temperatureof the solvent used. The reaction time may be 1 h to 48.

The compound of formula (IIIf-4) where all symbols are as definedearlier can be converted to corresponding methane sulfonate, p-toluenesulfonate, trifluoromethane sulfonate and the like. The intermediatesthus obtained are then subjected to hydrogenation following thecondition as described in route 7 and route 15 to yield compound offormula (IIIf) where all symbols are as defined above.

Route 31: The reduction of compound of the formula (IIIf-5) to yieldcompound of the general formula (IIIf) where R⁵ represents hydrogen andall other symbols are as defined above may be carried out in thepresence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C,Raney nickel and the like. Mixtures of catalysts may be used. Thereaction may also be conducted in the presence of solvents such asdioxane, acetic acid, ethyl acetate and the like. A pressure betweenatmospheric pressure and 80 psi may be employed. The catalyst may bepreferably 5-10% Pd/C and the amount of catalyst used may range from1-50% w/w. The reaction may also be carried out by employing metalsolvent reduction such as magnesium, iron, tin, samarium in alcohol orsodium amalgam in alcohol, preferably methanol or ethanol. Thehydrogenation may be carried out in the presence of metal catalystscontaining chiral ligands to obtain a compound of formula (IIIf) inoptically active form. The metal catalyst may contain Rhodium,Ruthenium, Indium and the like. The chiral ligands may preferably bechiral phosphines such as optically pure enantiomers of2,3-bis(diphenylphosphino)butane,2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane andthe like. (Ref: Principles of Asymmetric Synthesis, Tet. Org. ChemSeries Vol 14, pp 311-316, Ed. Baldwin J. E.).

In yet another embodiment of the present invention, the compound offormula (IIIf) where R² represents substituted or unsubstituted groupsselected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy;X represents NHR⁵, Y represents O, S, NR⁶ or CHR⁷, Z is as defined aboveexcluding NH and all other symbols are as defined above may be preparedby diazotizing the compound of formula (IIIf-6) to a compound of formula(IIIf-7) and reducing the compound of formula (IIIf-7) to yield compoundof formula (IIIf). The reaction shown in scheme-V below:

The diazotization of the compound of the formula (IIIf-6) where Z is asdefined above excluding NH and all other symbols are as defined above toobtain compound of formula (IIIf-7) where R² represents substituted orunsubstituted groups selected from alkoxy, aryloxy, aralkoxy,heteroaryloxy, heteroaralkoxy and all other symbols are as definedearlier may be carried out using diazotizing agent such as sodiumnitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and thelike under aqueous acidic conditions using acids such as sulfuric acid,HCl, acetic acid and the like, in an organic solvent such as alcoholssuch as methanol, ethanol, propanol and the like; 1,4-dioxane, THF,acetone and the like. Etherifying the residue obtained using alkylsulfates such as diethyl sulphate, dimethylsulphate and the like oralkyl halides such as ethyl iodide, methyliodide and the like, insolvents such as hydrocarbons like toluene, benzene and the like or DMF,DMSO, methyl isobutyl ketone (MIBK) and the like, in the presence ofalkali bases such as sodium carbonate, potassium carbonate, sodiummethoxide, sodium hydride, potassium hydride and the like.

The reduction of compound of the formula (IIIf-7) to yield a compound ofthe general formula (IIIf) where R⁵ represents hydrogen atom and allother symbols are as defined earlier may be carried out in the presenceof gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raneynickel and the like. Mixtures of catalysts may be used. The reaction mayalso be conducted in the presence of solvents such as dioxane, aceticacid, ethyl acetate and the like. A pressure between atmosphericpressure and 80 psi may be employed. The catalyst may be preferably5-10% Pd/C and the amount of catalyst used may range from 1-50% w/w. Thereaction may also be carried out by employing metal solvent reductionsuch as magnesium, iron, tin, samarium in alcohol or sodium amalgam inalcohol, preferably methanol. The hydrogenation may also be carried outusing ammonium formate, cyclohex-1,4-diene type of hydrogen donor underpd/c conditions using solvents such as methanol, ethanol, ethyl acetateand the like.

In yet another embodiment of the present invention, the compound offormula (IIIf) where R² represents substituted or unsubstituted groupsselected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy,X represents NHR⁵, Z is as defined above excluding NH and all othersymbols are as defined above may be prepared by diazotizing and reducingthe compound of formula (IIIf-6) to a compound of formula (IIIf-8) andetherifying the compound of formula (IIIf-8) to yield compound offormula (IIIf). The reaction shown in scheme-VI below:

The diazotization of the compound of the formula (IIIf-6) where allsymbols are as defined above to obtain compound of formula (IIIf-8) maybe carried out using diazotizing agent such as sodium nitrite, isoamylnitrite, potassium nitrite, ammonium nitrite and the like under aqueousacidic conditions using acids such as sulfuric acid, HCl, acetic acidand the like, in an organic solvent such as alcohols such as methanol,ethanol, propanol and the like; 1,4-dioxane, THF, acetone and the like.Reducing the residue obtained using gaseous hydrogen and a catalyst suchas Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalystsmay be used. The reduction may also be conducted in the presence ofsolvents such as dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50% w/w. The reaction may also be carried out byemploying metal solvent reduction such as magnesium, iron, tin, samariumin alcohol or sodium amalgam in alcohol, preferably methanol. Thehydrogenation may also be carried out using ammonium formate,cyclohex-1,4-diene type of hydrogen donor under pd/c conditions usingsolvents such as methanol, ethanol, ethyl acetate and the like.

The Etherification of compound of formula (IIIf-8) to yield compound offormula (IIIf) where R² represents substituted or unsubstituted groupsselected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxyand all other symbols are as defined earlier may be carried out usingalkyl sulfates such as diethyl sulphate, dimethylsulphate and the likeor alkyl halides such as ethyl iodide, methyliodide and the like, insolvents such as hydrocarbons like toluene, benzene and the like or DMF,DMSO, methyl isobutyl ketone (MIBK) and the like, in the presence ofalkali bases such as sodium carbonate, potassium carbonate, sodiummethoxide, sodium hydride, potassium hydride and the like.

In yet another embodiment of the present invention, the compound offormula (IIIf) where R² represents hydroxy or substituted orunsubstituted groups selected from alkoxy, aryloxy, aralkoxy,heteroaryloxy, heteroaralkoxy; X represents NHR⁵, Z is as defined aboveexcluding NH and all other symbols are as defined above may be preparedby following the process described in scheme-VII below:

The reaction of a compound of the general formula (IIIb) where allsymbols are as defined above with a compound of formula (IIIf-9) whereR¹² represents (C₁-C₆)alkyl group to yield compound of formula (IIIf-10)may be carried out in the presence of a base such as metal hydride likeNaH or KH; organolithiums such as CH₃Li, BuLi and the like; alkoxidessuch as NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixtures thereof. Thereaction may be carried out in the presence of solvents such as diethylether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like ormixtures thereof HMPA may be used as cosolvent. The reaction temperaturemay range from −78° C. to 50° C., preferably at a temperature in therange of −10° C. to 30° C.

The reduction of compound of the formula (IIIf-10) to yield a compoundof the formula (IIIf-2) may be carried out in the presence of gaseoushydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and thelike. Mixtures of catalysts may be used. The reaction may also beconducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate and the like. A pressure between atmospheric pressure and80 psi may be employed The catalyst may be preferably 5-10% Pd/C and theamount of catalyst used may range from 1-50% w/w. The reaction may alsobe carried out by employing metal solvent reduction such as magnesium,iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferablymethanol followed by an acidic work up. The hydrogenation may be carriedout in the presence of metal catalysts containing chiral ligands toobtain a compound of formula (I) in optically active form. The metalcatalyst may contain Rhodium, Ruthenium, Indium and the like. The chiralligands may preferably be chiral phosphines such as optically pureenantiomers of 2,3-bis(diphenylphosphino)butane,2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane andthe like.

The reaction of a compound of general formula (IIIf-2) with a compoundof formula (IIIf-3) where R⁵ is as defined above to yield compound offormula (IIIf) may be carried out using solvents such as CH₂Cl₂, CHCl₃,chlorobenzene, benzene, THF, in the presence of catalyst such asp-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF₃—OEt₂ andthe like. The reaction may also be carried out using activated molecularsieves. The temperature of the reaction may range from 10° C. to 100°C., preferably at a temperature in the range from 10° C. to 60° C. The,imine product initially produce may be reducing using Na(CN)BH₃—HCl(ref: Hutchins, R. O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428),H₂—Pd/C, H₂—Pt/C, H₂—Ph/C and the like in solvents such as methanol,ethanol and the like.

Alternatively, the reaction of compound of formula (IIIf-2) to yieldcompound of formula (IIIf) where R⁵ represents hydrogen, m is 1, and allother symbols are as defined above may be carried out using substitutedor unsubstituted hydroxylamine followed by treating with TiCl₃ asreagent and a reducing agent such as NaCNBH₃, or NaBH₄. The coactivatorslike ammonium acetate can be used. The reaction may be carried out inthe presence of solvents such as methanol, ethanol, water and the likeor mixtures thereof. The temperature of reaction may range from −20° C.to the reflux temperature of the solvent used. The reaction time may be1 h to 48.

Alternatively, the reaction of compound of formula (IIIf-2) to yieldcompound of formula (IIIf) where R⁵ represents hydrogen, m is 1, and allother symbols are as defined above may be carried out usingNH₃/methanol, NH₃/ethanol or NH₃/isopropanol in presence of Pd/C, Ra—Niand the like as catalyst and atmospheric pressure to 80 psi pressure ofhydrogen gas. The reaction temperature may range from room temperatureto 60° C. The duration of reaction may range from 2 h to 48.

In still another embodiment of the present invention the novelintermediate of formula (IIId)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate; R¹ represents hydrogen atom, halogen,hydroxy, alkyl, alkoxy, acyl, substituted or unsubstituted aralkylgroups; R² represents hydrogen, hydroxy, halogen, substituted orunsubstituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, aryl alkanoyl, alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy,heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl groups; R³ represents hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl or heteroaralkyl groups; Z represents oxygen orNR⁴, where R⁴ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, aryl aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl,aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups orR³ and R⁴ together may form a substituted or unsubstituted 5 or 6membered cyclic structure containing carbon atoms, a nitrogen atom andwhich may optionally contain one or two additional heteroatoms selectedfrom oxygen, sulfur or nitrogen; Ar represents substituted orunsubstituted, divalent, single or fused, aromatic, heteroaromatic orheterocyclic group; X represents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl or heteroaralkyl groups; Y represents O, S, NR⁶ or CHR⁷;where R⁶ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; R⁷ represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R¹; n is an integer in the range of 1-4; m and p areintegers ranging from 0-4 is provided.

In yet another embodiment of the present invention, the compound offormula (IIId) where X represents —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)NR⁵CO—; all symbols are as defined above may be prepared by aprocess which comprises, reacting the compound of formula (IIIf)

where X represents NHR⁵ and all other symbols are as defined above withcompound of formula (IIIId-1)L¹-(CH₂)_(n)—CO-L²  (IIId-1)where L¹ and n are as defined above and L² represents halogen atom.

The reaction of compound of formula (IIIf) with compound of formula(IIId-1) where may be carried out in the presence of solvents such asDCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere that may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be effected in the presence of a base such as triethylamine, lutidine, collidine and the like or mixtures thereof. Thereaction temperature may range from −20° C.-120° C. The duration of thereaction may range from 1 to 48 hours, preferably from 2 to 12 hours.

In still another embodiment of the present invention the novelintermediate of formula (IIId)

their derivatives, their analogs, their tautomeric forms, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates where L¹ is a leaving group such ashalogen, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate; R¹ represents hydrogen; R² representshydrogen, hydroxy, halogen, substituted or unsubstituted groups selectedfrom alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl,alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonylgroups; R³ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent singleor fused, aromatic, heteroaromatic or heterocyclic group; X representsO, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—;where R⁵ represents hydrogen or substituted or unsubstituted groupsselected from all, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl,aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Yrepresents O, S, NR⁶ or CHR⁷; where R⁶ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl or heteroaralkyl groups; R⁷ represents hydrogen atom,halogen, hydroxy, alkyl, alkoxy, substituted or unsubstituted aralkylgroup or forms a bond together with the adjacent group R¹; n is aninteger in the range of 1-4; m and p are integers ranging from 0-4 isprovided.

In yet another embodiment of the present invention, the compound offormula (IIId) where X represents —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)NR⁵CO—; all symbols are as defined above may be prepared by aprocess which comprises, reacting the compound of formula (IIIf)

where X represents NHR⁵ and all other symbols are as defined above withcompound of formula (IIId-1)L¹-(CH₂)_(n)—CO-L²  (IIId-1)where L¹ and n are as defined above and L² represents halogen atom.

The reaction of compound of formula (IIIf) with compound of formula(IIId-1) where may be carried out in the presence of solvents such asDCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere that may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be effected in the presence of a base such as triethylamine, lutidine, collidine and the like or mixtures thereof. Thereaction temperature may range from −20° C.-120° C. The duration of thereaction may range from 1 to 48 hours, preferably from 2 to 12 hours.

In still another embodiment of the present invention the novelintermediate of formula (IIId)

their derivatives, their analogs, their tautomeric forms, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates where L¹ is a leaving group such ashalogen, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate; R¹ represents hydrogen; R² representshydrogen, hydroxy, halogen, substituted or unsubstituted groups selectedfrom alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl,alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl alkylaminocarbonyl, arylaminocarbonylgroups; R³ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—,—(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Y represents O, S, NR⁶ or CHR⁷; where R⁶represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, substitutedor unsubstituted aralkyl group or forms a bond together with theadjacent group R¹; n is an integer in the range of 1-4; m and p areintegers ranging from 0-4 is provided.

In yet another embodiment of the present invention, the compound offormula (IIId) where X represents —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)NR⁵CO—; all symbols are as defined above may be prepared by aprocess which comprises, reacting the compound of formula (IIIf)

where X represents NHR⁵ and all other symbols are as defined above withcompound of formula (IIId-1)L¹-(CH₂)_(n)—CO-L²  (IIId-1)where L¹ and n are as defined above and L² represents halogen atom.

The reaction of compound of formula (IIIf) with compound of formula(IIId-1) where may be carried out in the presence of solvents such asDCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere that may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be effected in the presence of a base such as triethylamine, lutidine, collidine and the like or mixtures thereof. Thereaction temperature may range from −20° C.-120° C. The duration of thereaction may range from 1 to 48 hours, preferably from 2 to 12 hours.

In still another embodiment of the present invention the novelintermediate of formula (IIIa)A-G-(CH₂)_(n)—X—Ar—CHO  (IIIa)their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where Ar representssubstituted or unsubstituted, divalent, single or fused, aromatic,heteroaromatic or heterocyclic group; G represents O or S; X representsO, NHR⁵, —CO(CH₂)NR⁵(CH₂)_(m)—, (CH₂)_(p)O, —(CH₂)_(p)NR⁵CO—; where R⁵represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is aninteger in the range of 1-4; m and p are integers ranging from 0-4; Arepresents pyrazolopyrimidine or imidazolopyrimidine of the formulagiven below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives is provided.

In still another embodiment of the present invention the novelintermediate of formula (IVb)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like; R¹ represents hydrogen atom,halogen, hydroxy, alkyl, alkoxy, acyl, substituted or unsubstitutedaralkyl groups; R³ represents hydrogen or substituted or unsubstitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl or heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups or R³ andR⁴ together may form a substituted or unsubstituted 5 or 6 memberedcyclic structure containing carbon atoms, a nitrogen atom and which mayoptionally contain one or two additional heteroatoms selected fromoxygen, sulfur or nitrogen; Ar represents substituted or unsubstituted,divalent, single or fused, aromatic, heteroaromatic or heterocyclicgroup; G represents O or S; X represents O, NHR⁵,—CO(CH₂)_(p)NR⁵(CH₂)_(m)—, (CH₂)_(p)O, —(CH₂)_(p)NR⁵CO—; where R⁵represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Yrepresents O, S, NR⁶ or CHR⁷; where R⁶ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl or heteroaralkyl groups; R⁷ represents hydrogen atom,halogen, hydroxy, alkyl, alkoxy, substituted or unsubstituted aralkylgroup or forms a bond together with the adjacent group R¹; m and p areintegers ranging from 0-4; n is an integer in the range of 1-4; Arepresents pyrazolopyrimidine or imidazolopyrimidine of the formulagiven below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives is provided.

In still another embodiment of the present invention the novelintermediate of formula (IVf)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; Arrepresents substituted or unsubstituted, divalent, single or fused,aromatic, heteroaromatic, or heterocyclic group; G represents O or S; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)—, (CH₂)_(p)O, —(CH₂)_(p)NR⁵CO—;where R⁵ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; Y represents O, S, NR⁶ or CHR⁷; where R⁶ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl heterocyclyl,heteroaryl or heteroaralkyl groups; R⁷ represents hydrogen atom,halogen, hydroxy, alkyl, alkoxy, substituted or unsubstituted aralkylgroup or forms a bond together with the adjacent group R¹; m and p areintegers ranging from 0-4; n is an integer in the range of 1-4; Arepresents pyrazolopyrimidine or imidazolopyrimidine of the formulagiven below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoylaroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonylaryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives is provided.

In still another embodiment of the present invention the novelintermediate of formula (IVg)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R³ representshydrogen or substituted or unsubstituted groups selected from alkyl,cycloalkyl, aryl aralkyl, heterocyclyl, heteroaryl or heteroaralkylgroups; Z represents oxygen or NR⁴, where R⁴ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl or heteroaralkyl groups or R³ and R⁴ together may form asubstituted or unsubstituted 5 or 6 membered cyclic structure containingcarbon atoms, a nitrogen atom and which may optionally contain one ortwo additional heteroatoms selected from oxygen, sulfur or nitrogen; Arrepresents substituted or unsubstituted, divalent, single or fused,aromatic, heteroaromatic or heterocyclic group; G represents O or S; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, (CH₂)_(p)O,—(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, alkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl,heteroaralkyl groups or (C₁-C₁₂)alkylcarboxylic acid and itsderivatives; Y represents O, S, NR⁶ or CHR⁷; where R⁶ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷ represents hydrogenatom, halogen, hydroxy, alkyl, alkoxy, substituted or unsubstitutedaralkyl group; m and p are integers ranging from 0-4; n is an integer inthe range of 1-4; A represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives is provided.

It is appreciated that in any of the above mentioned reactions, anyreactive group in the substrate molecule may be protected according toconventional chemical practice. Suitable protecting groups in any of theabove mentioned reactions are tertiarybutyldimethylsilyl, methoxymethyl,triphenyl methyl, benzyloxycarbonyl, THP etc, to protect hydroxyl orphenolic hydroxy group; N-Poc, Boc, N-Cbz, N-Fmoc, benzophenoneimineetc, for protection of amino or anilino group, acetal protection foraldehyde, ketal protection for ketone and the like. The methods offormation and removal of such protecting groups are those conventionalmethods appropriate to the molecule being protected.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula (I) with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium hydroxide,potassium t-butoxide, calcium hydroxide, magnesium hydroxide and thelike, in solvents like ether, THF, methanol, t-butanol, dioxane,isopropanol, ethanol, toluene etc. Mixtures of solvents may be used.Organic bases like lysine, arginine, diethanolamine, choline, guanidine,adamentyl amine and their derivatives etc. may also be used.Alternatively, acid addition salts wherever applicable are prepared bytreatment with acids such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid,methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylicacid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinicacid, benzoic acid, benzenesulfonic acid, tartaric acid and the like insolvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane andthe like. Mixtures of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where ZR³represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with chiral amines, aminoacids, aminoalcohols derived fromaminoacids; conventional reaction conditions may be employed to convertacid into an amide; the diastereomers may, be separated either byfractional crystallization or chromatography and the stereoisomers ofcompound of formula (I) may be prepared by hydrolyzing the purediastereomeric amide.

Various polymorphs of a compound of general formula (I) forming part ofthis invention may be prepared by crystallization of compound of formula(I) under different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe NMR spectroscopy, IR spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The present invention provides a pharmaceutical composition, containingthe compounds of the general formula (I) as defined above, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts or theirpharmaceutically acceptable solvates in combination with the usualpharmaceutically employed carriers, diluents and the like are useful forthe treatment and/or prophylaxis of diseases such as hypertension,coronary heart disease, atherosclerosis, stroke, peripheral vasculardiseases and related disorders. These compounds are useful for thetreatment of hyperlipemeia, hyperglycemia, familialhypercholesterolemia, hypertriglyceridemia, lowering of atherogeniclipoproteins, VLDL and LDL. The compounds of the present invention canbe used for the treatment of certain renal diseases includingglomenrulonephritis, glomerulosclerosis, nephrotic syndrome,hypertensive nephrosclerosis, nephropathy. The compounds of generalformula (I) are also useful for the treatment/prophylaxis of insulinresistance (type II diabetes), leptin resistance, impaired glucosetolerance, dyslipidemia, disorders related to syndrome X such ashypertension, obesity, insulin resistance, coronary heart disease, andother cardiovascular disorders. These compounds may also be useful asaldose reductase inhibitors, for improving cognitive functions indementia, treating diabetic complications, disorders related toendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy,pancreatitis, retinopathy, arteriosclerosis, xanthoma, inflammation andfor the treatment of cancer. The compounds of the present invention arealso useful in the treatment and/or prophylaxis of the above saiddiseases in combination/concomittant with one or more HMG CoA reductaseinhibitors, hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramine, colestipol, probucol ortheir combination. The compounds of the present invention in combinationwith HMG CoA reductase inhibitors, hypolipidemic/hypolipoproteinemicagents can be administered together or within such a period to actsynergistically. The HMG CoA reductase inhibitors may be selected fromthose used for the treatment or prevention of hyperlipidemia such aslovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin,cerivastatin and their analogs thereof. Suitable fibric acid derivativemay be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrateand their analogs thereof.

The present invention also provides a pharmaceutical composition,containing the compounds of the general formula (I) as defined above,their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptable saltsor their pharmaceutically acceptable solvates and one or more HMG CoAreductase inhibitors, hypolipidemic/hypolipoproteinemic agents such asfibric acid derivatives, nicotinic acid, cholestyramine, colestipol,probucol in combination with the usual pharmaceutically employedcarriers, diluents and the like.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain flavorants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 20%, preferably 1 to 10% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active ingredientwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compound of formula (I) can becombined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, powders, syrups, solutions, suspensions and the like.The pharmaceutical compositions, may, if desired, contain additionalcomponents such as flavourants, sweeteners, excipients and the like. Forparenteral administration, the compound formula (I) can be combined withsterile aqueous or organic media to form injectable solutions orsuspensions. For example, solutions in sesame or peanut oil, aqueouspropylene glycol and the like can be used, as well as aqueous solutionsof water-soluble pharmaceutically-acceptable acid addition salts orsalts with base of the compounds. Aqueous solutions with the activeingredient dissolved in polyhydroxylated castor oil may also be used forinjectable solutions. The injectable solutions prepared in this mannercan then be administered intravenously, intraperitoneally,subcutaneously, or intramuscularly, with intramuscular administrationbeing preferred in humans.

For nasal administration, the preparation may contain the compound offormula (I), of the present invention dissolved or suspended in a liquidcarrier, in particular an aqueous carrier, for aerosol application. Thecarrier may contain additives such as solubilizing agents, such aspropylene glycol, surfactants, absorption enhancers such as lecithin(phosphatidylcholine) or cyclodextrin or preservatives such asparabenes.

Tablets, dragees or capsules having talc and/or a carbohydrate carriedbinder or the like are particularly suitable for any oral application.Preferably, carriers for tablets, dragees or capsules include lactose,corn starch and/or potato starch. A syrup or elixir can be used in caseswhere a sweetened vehicle can be employed.

A typical tablet production method is exemplified below:

Tablet Production Example a) 1) Active ingredient  30 g 2) Lactose  95 g3) Corn starch  30 g 4) Carboxymethyl cellulose  44 g 5) Magnesiumstearate  1 g 200 g for 1000 tablets

The ingredients 1 to 3 are uniformly blended with water and granulatedafter drying under reduced pressure. The ingredient 4 and 5 are mixedwell with the granules and compressed by a tabletting machine to prepare1000 tablets each containing 30 mg of active ingredient. b) 1) Activeingredient  30 g 2) Calcium phosphate  90 g 3) Lactose  40 g 4) Cornstarch  35 g 5) Polyvinyl pyrrolidone  3.5 g 6) Magnesium stearate  1.5g 200 g for 1000 tablets

The ingredients 1-4 are uniformly moistened with an aqueous solution of5 and granulated after drying under reduced pressure. Ingredient 6 isadded and granules are compressed by a tabletting machine to prepare1000 tablets containing 30 mg of ingredient 1.

The compound of the formula (I) as defined above are clinicallyadministered to mammals, including man, via either oral, nasal,pulmonary, transdermal or parenteral, rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmicsolution or an ointment. Administration by the oral route is preferred,being more convenient and avoiding the possible pain and irritation ofinjection. However, in circumstances where the patient cannot swallowthe medication, or absorption following oral administration is impaired,as by disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.01 to about 100 mg/kg body weight of the subject per day orpreferably about 0.01 to about 30 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

Preparation 1

Ethyl 2-bromopentanoate

Red phosphorous (455 mg, 14.7 mmol) was added to valeric acid (15 g,14.7 mmol) followed by drop wise addition of bromine (15 mL, 294 mmol)at room temperature. After complete addition, the reaction mixture washeated to 100° C. for 6 h. The excess bromine was then removed usingwater aspirator at the same temperature. Ethanol (25 mL) was added tothe residue and refluxed for overnight. The reaction mixture was cooledto room temperature and poured into water (45 mL) when oil separated.The oil was washed with water, saturated sodium bicarbonate and water,dried (Na₂SO₄) and distilled under reduced pressure to obtain the titlecompound (26.2 g, 85%) as colorless oil.

¹H NMR (CDCl₃): δ 0.94 (t, J=7.3 Hz, 3H), 1.29 (t, 3=7.1 Hz, 3H),1.35-1.56 (m, 2H), 1.90-2.13 (m, 2H), 4.15-4.29 (m, 3H).

Preparation 2

Ethyl 2-(4-aminophenylsulfanyl)pentanoate

To a cooled solution of 4-aminothiophenol (5.40 g, 43.2 mmol) inN,N-dimethylformamide (30 mL) sodium hydride (60% oil coated, 1.9 g,47.5 mmol) was added portion wise. After stirring at room temperaturefor 30 min ethyl 2-bromopentanoate (14.44 g, 69.1 mmol), obtained inpreparation 1, in N,N-dimethylformamide (25 mL) was added to the abovereaction mixture at 0° C. with vigorous stirring. The stirring wascontinued at room temperature for further 48 h. The reaction mixture wasdiluted with ethyl acetate (400 mL) and washed the organic layersuccessively with water (300 mL) and brine, dried over anhydrous sodiumsulfate and concentrated. The residue was purified by columnchromatography using 10% ethyl acetate in pet ether to afford the titlecompound (6.04 g, 55.3%) as yellow oil.

¹H NMR (CDCl₃): δ 0.90 (t, J=7.0 Hz, 311), 1.24 (t, J=7.1 Hz, 3H),1.30-1.55-1.91 (m, 2H), 3.42 (dd, J=8.1 and 6.6 Hz, 1H), 4.09 (q, J=7.1Hz, 2H) 8.8 Hz, 2H), 7.26 (d, 3=8.3 Hz, 2H).

Preparation 3

Ethyl 2-(4-heptylaminophenylsulfanyl)pentanoate

The title compound (586 mg, 14.25%) was obtained as light brown coloredliquid from ethyl 2-(4-amionophenylsulfanyl)pentanoate (2.96 g, 11.7mmol) obtained in preparation 2, heptyl bromide (2 mL, 12.9 mmol) andsodium hydride (60% oil coated, 516 mg, 12.9 mmol) by following thesimilar procedure as described in preparation 2.

¹H NMR (CDCl₃): δ 0.92-1.00 (m, 6H), 1.21 (t, J=7.1 Hz, 3H), 1.30-1.88(m, 14H), 3.10 (t, 3=7.1 Hz, 2H), 3.41 (dd, J=8.3 and 6.8 Hz, 1H), 4.10(q, J=7.2 Hz, 2H), 6.52 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H).

Preparation 4

Ethyl 2-[4-chloromethyl(heptyl)carboxamidophenylsulfanyl]pentanoate

To a cooled solution of ethyl 2-(4-heptylaminophenylsulfanyl)pentanoate(586 mg, 1.66 mmol), obtained in preparation 3, in dichloromethane (10mL) triethyl amine (0.58 mL, 4.17 mmol) was added drop wise. Afterstirring at room temperature for 15 min chloroacetyl chloride (0.3 mL,3.77 mmol) was added at 0° C. and the stirring was continued at roomtemperature for further 12 h. The reaction mixture was diluted withdichloromethane (10 mL) and washed the organic layer successively withwater (10 mL) and brine, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by column chromatography using 8%ethyl acetate in pet ether to afford the title compound (597 mg, 84%) asoil.

¹H NMR (CDCl₃): δ 0.88 (t, J=6.1 Hz, 3H), 0.98 (t, J=7.3 Hz, 3H),1.15-1.60 (m, 15H), 1.71-2.03 (m, 2H), 3.65-3.88 (m, 5H), 4.17 (q, J=7.2Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H).

Preparation 5

Ethyl(2S)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate

Step-i:

4-Hydroxybenzaldehyde (100 g), potassium carbonate (226 g) anddimethylformamide (500 ml) were taken in a reaction flask and stirredfor 15 minutes. Benzylchloride (114 g) was then added at roomtemperature and the reaction mass was stirred at the same temperaturefor a period of 8-10 h. The progress of the reaction was monitored withTLC. After completion of the reaction, the reaction mixture was dumpedinto ice water and extracted with toluene. The combined organic extractswere washed with 10% aq. sodium hydroxide solution followed by water.The solvent was removed under reduced pressure and the resulting residuewas triturated with pet. ether to afford 4-benzyloxybenzaldehyde(160-165 g, 93-95%).

Step-ii:

4-Benzyloxybenzaldehyde obtained in step (i) above, was added to asolution of sodium ethoxide (64 g) in absolute ethanol followed by theaddition of ethylchloroacetate (87 g) over a period of 30-45 minutes,maintaining ambient temperature. The reaction mixture was stirred at thesame temperature for 3-5 h. The progress of the reaction was monitoredwith TLC. After completion of the reaction, the reaction mixture wasdumped into ice water and stirred for 5-10 minutes. The solid thusobtained was filtered, washed with water and dried to affordethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate (126-129 g, 90-92%).

Step-iii:

A mixture of ethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate (125 g)obtained in step (ii) above, 5% Pd/C catalyst (12.5 g) and 1,4-dioxane(750 ml) was hydrogenated at room temperature at 5-10 psi of hydrogenpressure for a period of 10-15 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the catalyst wasfiltered and the solvent was removed under reduced pressure to affordracemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate (100-105 g,80-83%).

Step-iv:

A mixture of racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate(100 g) obtained in step (iii) above and 10% aq. sodium hydroxidesolution (500 ml) was stirred at room temperature for a period of 1-2 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was acidified with dil. hydrochloricacid at 15-20° C. and the solid thus obtained was filtered and washedwith water to afford racemic 2-hydroxy-3-(4-benzyloxyphenyl)propionicacid (72-77 g, 80-85%).

To a solution of racemic 2-hydroxy-3-(4-benzyloxyphenyl)propionic acid(75 g) obtained according to the procedure described above inethylacetate (1.1 L) was added R(+)-α-methylbenzylamine (33 g) and themixture was stirred at room temperature for a period of 2-4 h. The solidthus obtained was filtered and the acid was regenerated afteracidification to afford S(−)-2-hydroxy-3-(4-benzyloxyphenyl)propionicacid of the formula (11), (33-35 g, 44-47%). The R(+)-α-hydroxy acidobtained from the mother liquor was racemised and mixed with subsequentbatches for resolution. The overall yield obtained by several suchreprocesses was 90-95%.

Step-v:

To a slurry of sodium hydride (60% suspension in oil, 13 g) and dimethylformamide (70 ml) was added a solution ofS(−)-2-hydroxy-3-(4-benzyloxyphenyl)propionic acid (35 g) obtained instep (iv) above, in dimethylformamide (105 ml) at 5-10° C. over a periodof 15-30 minutes. The temperature was allowed to attain room temperatureand maintained at the same temperature for 1-3 hours. Ethyl iodide (62g) was added slowly by maintaining the temperature at 25-30° C. over aperiod of 2-3 hours. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was dumped intoice water and extracted with toluene. The combined organic extracts werewashed with water and the solvent was removed under reduced pressure toafford S(−)-ethyl 2-ethoxy-3-(4-benzyloxyphenyl)propionate (41-42 g,98-99%).

Step-vi:

A mixture of S(−)-ethyl 2-ethoxy-3-4-benzyloxyphenyl)propionate (40 g)obtained in step (v) above, 5% Pd/C catalyst (8 g) and tetrahydrofuran(120 ml) was subjected to hydrogenation at room temperature and 50-60psi of hydrogen pressure for a period of 8-12 hours. After completion ofthe reaction, the catalyst was filtered off and the solvent was removedunder reduced pressure to afford S(−)-ethyl2-ethoxy-3-(4-hydroxyphenyl)propionate (28-29 g, 97-98%).

Step-vii:

Ethyl(2S)-3-(4-hydroxyphenyl)-2-ethoxypropanoate obtained in step viabove (18 g, 75.63 mmol) and anhydrous K₂CO₃ (31.14 g, 225.65 mmol) werebrought to reflux temperature in dry acetone (180 mL). 1,2-Dibromoethane(32.58 mL, 377.45 mmol) was added to the reaction mixture at refluxtemperature and refluxed for 48 h. Solid K₂CO₃ was filtered off and thefiltrate was concentrated under vacuum. The residue was dissolved inethyl acetate and washed with water, dried (Na₂SO₄) and concentrated.The residue was chromatographed on silica gel using 10% ethyl acetate inpet ether to yield the title compound (12.5 g, 47.9%) as liquid and thestarting material was recovered (6 g), mp 170-173° C.

[α]_(D) ²⁵=−14.0° (c=1.0, CH₃OH).

¹H NMR (CDCl₃): δ 1.18 (t, J=6.8 Hz, 3H), 1.25 (t, 3=6.8 Hz, 3H), 2.96(d, J=6.8 Hz, 2H), 3.28-3.47 (m, 1H), 3.51-3.88 (m, 3H), 3.98 (t, J=6.6HZ, 1H), 4.18 (q, J=7.1 Hz, 2H), 4.28 (t, J=6.3 Hz, 2H), 6.84 (d, J=8.8Hz, 2H), 7.1 (d, J=8.3 Hz, 2H).

Preparation 6

2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propanoic Acid

Step i:

A solution of triethyl-2-ethoxyphosphonoacetate prepared (5.61 g, 20.89mmol) in dry tetrahydrofuran (20 mL) was added slowly to a stirred icecooled suspension of sodium hydride (60% dispersion of oil) (1 g, 42mmol) in dry tetrahydrofuran (10 mL), under a nitrogen atmosphere. Themixture was stirred at 0° C. for 30 min. prior to the addition of a4-(2-bromoethoxy)benzaldehyde (4.0 g, 17.4 mmol) in dry tetrahydrofuran(30 mL). The mixture was allowed to warm up to room temperature andstirred at that temperature for further 20 h. The solvent wasevaporated, water (100 mL) was added and extracted with ethyl acetate(2×75 mL). The combined organic extracts were washed with water (50 mL),brine (50 mL), dried (Na₂SO₄), filtered and the solvent was evaporatedunder reduced pressure. The residue was chromatographed over silica gelusing a mixture of ethyl acetate and pet. ether (2:8) as an eluent toafford ethyl(E/Z)-3-[4-2-bromoethoxy)phenyl]-2-ethoxypropenoate (4.0 g,66%) as an oil in 45:55 ratio of E:Z isomers (as measured by ¹H NMR).

¹H NMR (CDCl₃, 200 MHz): δ 1.17 and 1.42 (6H, E and Z triplets, isomericOCH₂CH₃ and OCH₂CH₃), 3.62-3.72 (complex, 2H), 3.90-4.28 (complex, 2H),4.30-4.37 (complex, 4H), 6.09 (s, 0.45H, olefinic proton of E isomers),6.85 and 6.92 (2H, d and d, J=8.67 Hz and 8.7 Hz), 6.98 (s, 0.55H, Zisomer of olefinic proton), 7.16 and 7.78 (d and d, combined 2H, J=8.63Hz and 8.72 Hz).

Step ii.

Ethyl(E/Z)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropenoate obtained instep i. above (5.0 g, 14.5 mmol) and H₂/10% Pd—C (4 g) in dioxane (50ml) was stirred at 25° C. under 60 psi hydrogen pressure for 24 h. Thecatalyst was filtered and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether (2:8) as an eluent to affordethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (4.0 g, 80%) as acolorless oil.

¹H NMR (CDCl₃, 200 MHz): δ 1.12-1.36 (complex, 6H), 2.95 (d, J=6.64 Hz,2H), 3.25-3.45 (complex, 1H), 3.56-3.68 (complex, 3H), 3.96 (t, J=6.65Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 4.27 (t, J=6.3 Hz, 2H), 6.81 (d, J=8.67Hz, 2H), 7.16 (d, J=8.63 Hz, 2H).

Step iii.

Method A: Ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate obtainedin step ii. above (1.7 g, 4.93 mmol) was taken in potassium hydroxidesolution (1.1 g, 19.71 mmol in 18 mL of water) and stirred at roomtemperature for 24 h. Then the reaction mixture was heated to 80-85° C.for 4-5 days. The reaction mixture was cooled to 0° C. and acidifiedwith 2N HCl solution to pH ˜2 and extracted with ethyl acetate (3×50mL). The combined organic extracts were washed with brine, dried(Na₂SO₄) and evaporated to dryness. The residue was purified by columnchromatography on silica gel using 25% pet ether in ethyl acetate toafford the title compound (0.93 g, 74%).

Method B: To a solution of ethyl3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate obtained in step ii.above (2.5 g, 7.25 mmol) in methanol (40 mL) was added a solution ofsodium carbonate (3.84 g, 36.2 mmol) in water (20 mL), and stirred thereaction mixture for 24 h at room temperature. Methanol was removedunder reduced pressure and the residue was diluted with water (50 mL)and extracted with ethyl acetate (2×50 mL) to remove impurities, if any.The aqueous layer was cooled to 0° C. and acidified with 2N HCl solutionto pH-2 and extracted with ethyl acetate (2×200 mL). The organicextracts were washed with brine, dried (Na₂SO₄) and evaporated todryness to give the crude intermediate (2.2 g, 96%).

The crude residue (2.2 g) was dissolved in potassium hydroxide solution(1.56 g in 20 mL of water) and the reaction mixture was stirred at roomtemperature for 96 h. The reaction mixture was cooled to 0° C. andacidified with 2N HCl solution to pH ˜2 and extracted with ethyl acetate(3×100 mL). The combined organic extracts were washed with brine, dried(Na₂SO₄) and evaporated to dryness. The residue was purified by columnchromatography on silica gel using 25% pet ether in ethyl acetate toafford the title compound (1.5 g, 81%).

¹H NMR (CDCl₃): δ 1.19 (t, J=7.1 Hz, 3H), 2.88-3.18 (m, 2H), 3.39-3.70(m, 2H), 3.93-4.25 (m, 5H), 6.86 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz,2H).

Preparation 7

Ethyl 2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propanoate

To a cooled solution of 2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propanoicacid obtained in preparation 6 (0.92 g, 3.62 mmol) in ethanol (10 mL),conc. H₂SO₄ (1 mL) was added slowly and the reaction mixture wasrefluxed for 6 h. Ethanol was removed under reduced pressure. Theresidue was taken in ethyl acetate (100 mL), washed with saturatedsodium bicarbonate solution, water, brine and dried over Na₂SO₄, andconcentrated. The residue was purified on silica gel column using 10%ethyl acetate in pet ether to afford the title compound (0.72 g, 70.5%).

¹H NMR (CDCl₃): δ 1.16 (t, J=6.8 Hz, 3H), 1.22 (t, J=6.8 Hz, 3H), 2.95(d, J=6.3 Hz, 2H), 3.27-3.42 (m, 1H), 3.51-3.70 (m, 1H), 3.92-4.08 (m,5H), 4.16 (q, J=7.2 Hz, 2H), 6.83 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.8 Hz,2H).

Preparation 8

(2S)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propanoic Acid

The title compound (0.72 g, 49%) was prepared fromethyl(2S)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate obtained inpreparation 5 (2 g, 5.8 mmol) by following similar procedure asdescribed in preparation 6, method B.

¹H NMR (CDCl₃): δ 1.17 (t, J=7.1 Hz, 3H), 2.90-3.15 (m, 2H), 3.39-3.70(m, 2H), 3.95 (t, J=4.1 Hz, 21), 3.99-4.19 (m, 3H), 6.84 (d, J=8.3 Hz,2H), 7.16 (d, J=8.8 Hz, 2H).

Preparation 9

Ethyl(2S)-2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propanoate

The title compound (0.37 g, 48%) was prepared from(2S)-2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propanoic acid obtained inpreparation 8 (0.7 g, 2.76 mmol) by following the similar procedure asdescribed in preparation 7.

[α]_(D) ²⁵=−17.8° (c=0.5, CHCl₃).

¹H NMR (CDCl₃): δ 1.16 (t, J=6.8 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 2.95(d, J=6.4 Hz, 2H), 3.26-3.43 (m, 1H), 3.51-3.69 (m, 1H), 3.92-4.10 (m,51), 4.17 (q, J=7.2 Hz, 2H), 6.84 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.3 Hz,2H).

Preparation 10

4-Aminobenzoyl-1-methyl-3-propyl-1H-pyrazole-5-carboxamide

Step i.

Sodium (11.5 g, 500 mmol) was added to ethanol (130 mL) in portions atroom temperature with vigorous stirring. After sodium got dissolved, thesolution was cooled to 0° C. Methyl propyl ketone (53.0 mL, 500 mmol)was added dropwise and the stirring was continued for further 15-20 min.Diethyl oxalate (68.0 mL, 500 mmol) was added dropwise to the resultingsolution at 0° C. and the stirring was continued for another 15 min at0° C. The reaction mixture was then allowed to attain room temperatureand the stirring was continued for further 12 h at this temperature. Thereaction mixture was then kept in refrigerator for 24 h. The solvent wasremoved under vacuum at room temperature. The resulting residue wasdiluted with dil. hydrochloric acid on an ice bath and extracted theaqueous layer with diethyl ether (4×50 mL). The combined ether extractswere washed with water, brine, dried (Na₂SO₄) and concentrated undervacuum. The crude mass was chromatographed on silica gel using 3% ethylacetate in pet ether as eluent to yield ethyl 2,4-dioxoheptanoate (60.0g, 64.5%).

¹H NMR (CDCl₃): δ 14.45 (broad s, D₂O exchangeable, 1H), 6.33 (s, 1H),4.32 (q, J=7.10 Hz, 2H), 2.44 (t, J=7.40 Hz, 2H), 1.72-1.57 (m, 2H),1.35 (t, J=7.30 Hz, 3H), 0.94 (t, J=7.40 Hz, 3H).

Step ii.

To a stirred mixture of ethyl 2,4-dioxoheptanoate (28.0 g, 150 mmol)obtained in step i. above, acetic acid (225 mL) and methoxy ethanol (225mL), hydrazine hydrochloride (31.6 g, 300 mmol) was added and heated to105° C. for 3 h. Acetic acid and methoxy ethanol were removed undervacuum at 90° C. The residue was taken in water and extracted threetimes with ethyl acetate. The combined organic layers were washed withwater, brine, dried (Na₂SO₄) and concentrated to obtain solids suspendedin liquid. The filtrate was evaporated to yield Ethyl3-propyl-1H-5-pyrazole carboxylate (16.0 g, 58.4%) as liquid.

¹H NMR (2A) (CDCl₃): δ 6.57 (s, 1H), 4.34 (q, J=7.10 Hz; 2H), 2.65 (t,J=7.50 Hz, 2H), 1.71-1.59 (m, 2H), 1.33 (t, J=7.20 Hz, 3H), 0.92 (t,J=7.30 Hz, 3H).

Step ii.

Dimethyl sulfate (6.0 g, 48.35 mmol) was added to the pyrazole esterobtained in step ii. above (16.0 g, 88 mmol) and the reaction mixturewas heated at 160° C. for 2 h. The reaction mixture was cooled to ˜90°C. and 5N sodium hydroxide solution (64 mL) was added and the reactionmixture was stirred at 80-90° C. for 30 min. The reaction mixture wascooled in an ice bath and was acidified to pH 4 with 2N hydrochloricacid resulting precipitation of the product. The precipitate wasfiltered, washed with cold water and dried under vacuum to yield1-Methyl-3-propyl-1H-5-pyrazole carboxylic acid (12.0 g, 81%). ¹HNMR(CDCl₃): δ 6.70 (s, 1H), 4.14 (s, 3H), 2.64 (t, J=7.60 Hz, 2H),1.72-1.61 (m, 2H), 0.95 (t, J=7.30 Hz, 3H).

Step iv.

Nitrating agent was prepared by adding 90% nitric acid (7.18 mL) toconcentrated sulphuric acid (13.8 mL) at 75-78° C.1-Methyl-3-propyl-1H-5-pyrazole carboxylic acid (11.5 g, 68.4 mmol)obtained in step iii. above was added to the nitrating agent portionwise with stirring so that the temperature is maintained at ˜85° C.After the complete addition, the mixture was heated at 100° C. for 2 h.The reaction mixture was cooled and poured into crushed ice. Thesuspension was filtered cold (10° C.) and the solids were washed withice cold brine and dried to yield1-Methyl-4-nitro-3-propyl-1H-5-pyrazole carboxylic acid (5.0 g, 34%).

¹H NMR (CDCl₃): δ 6.90 (broad s, D₂O exchangeable, 1H), 4.20 (s, 3H),2.90 (t, J=7.60 Hz, 2H), 1.79-1.64 (m, 2H), 1.02 (t, J=7.40 Hz, 3H).

Step v.

Thionyl chloride (7.2 mL, 98 mmol) was added to1-methyl-4-nitro-3-propyl-1H-5-pyrazole carboxylic acid obtained in stepiv. (3.3 g, 15.5 mmol) and refluxed for 3.5 h. The excess thionylchloride was removed from the reaction mixture under vacuum and theresidue was taken in dry acetone (20 mL). Ammonia gas was passed throughthis solution till pH reached 8-9. The precipitate formed was filtered.The filtrate was concentrated and then dissolved in ethyl acetate. Theorganic phase was washed with water, brine, dried (Na₂SO₄) andconcentrated to yield 1-Methyl-4-nitro-3-propyl-1H-5-pyrazolecarboxamide as a fluffy material (3.1 g, 94%).

¹H NMR (CDCl₃): δ 7.50 (broad s, D₂O exchangeable, 1H), 6.08 (broad s,D₂O exchangeable, 1H), 4.05 (s, 31), 2.86 (t, J=7.70 Hz, 2H), 1.75-1.60(m, 2H), 0.98 (t, J=7.30 Hz, 3H).

Step vi.

To a solution of 1-methyl-4-nitro-3-propyl-1H-5-pyrazole carboxamideobtained in step v. (3.2 g, 15.0 mmol) in methanol (30 mL), Raney nickel(450 mg) was added and hydrogenated by passing hydrogen gas at 50 psifor 10 h. The reaction mixture was filtered through celite bed andwashed with methanol. The filtrate and washings were combined,concentrated, purified by silica gel column chromatography using ethylacetate-pet. ether (1:1) as eluent to yield4-amino-1-methyl-3-propyl-1H-5-pyrazole carboxamide (2.0 g, 73%).

¹H NMR (CDCl₃): δ 7.05 (broad s, D₂O exchangeable, 2H), 4.07 (s, 3H),2.75 (broad s, D₂O exchangeable, 2H), 2.51 (t, J=7.60 Hz, 2H), 1.69-1.50(m, 2H), 0.95 (t, J=7.30 Hz, 3H).

Step vii.

To a solution of 4-amino-1-methyl-3-propyl-1H-5-pyrazole carboxamideobtained in step vi. above (550 mg, 3.0 mmol) in dichloromethane (8 mL)triethyl amine (0.92 mL, 6.6 mmol) was added at 0° C. and the reactionmixture was stirred for 15 min. Benzoyl chloride (0.39 mL, 3.32 mmol)was added drop wise at 0° C. and the stirring was continued for further1 h at the same temperature. The reaction mixture was diluted withdichloromethane and washed successively with water and brine, dried(Na₂SO₄) and concentrated to give the title compound (680 mg, 70%) as asolid, mp 140° C.

¹H NMR (CDCl₃): δ 0.92 (t, J=7.6 Hz, 31), 1.50-1.75 (m, 2H), 2.51 (t,J=7.6 Hz, 2H), 3.95 (s, 3H), 7.35-7.65 (m, 31), 7.91 (d, 3=7.5 Hz, 2H).

Preparation 11

1-Methyl-5-phenyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one

To a stirred solution of potassium tert-butoxide (440 mg, 4.4 mmol) int-butanol (10 mL)4-aminobenzoyl-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1.0 g, 3.67mmol), obtained in the preparation 10, was added portion wise and thereaction mixture was refluxed for 6 h. The solvent was removed undervacuum and the resulting residue was diluted with water and acidifiedwith dil. HCl to pH˜5 at 0° C. The resulting white precipitate wasfiltered, washed with water and dried to afford the title compound (700mg, 74.7%).

¹H NMR (CDCl₃): δ 1.02 (t, J=7.3 Hz, 311), 1.79-2.10 (m, 2H), 2.93 (t,J=7.5 Hz, 2H), 4.27 (s, 3H), 7.5.1 (br s, 3H), 8.10-8.17 (m, 2H).

Preparation 12

1-Methyl-3-propyl-5-cyclopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-one

Cyclopropane carboxylic acid (600 mg, 6.97 mmol) was refluxed in thionylchloride (1.01 mL, 1.64 mmol) for 2 h. Excess thionyl chloride wasdistilled off and the acid chloride was cooled to 0° C. In another setup, to a solution of 4-amino-1-methyl-3-propyl-1H-5-pyrazole carboxamide(prepared as disclosed in our U.S. application Ser. No. 09/507,373) (1.0g, 5.49 mmol) in xylene (10 mL), cyclopropane carboxylic acid (5 mL) wasadded and cooled in ice bath. Triethyl amine was added to the abovemixture and stirred for 20 min. This mixture was then added to acidchloride at 0° C. and stirred at room temperature for 1 h. The reactionmixture was refluxed for 48 h and the solvents were removed underreduced pressure. The residue was diluted with water and extracted withethyl acetate (3×60 mL). The combined organic layers were washed withwater, brine, dried (Na₂SO₄) and concentrated. The crude compound waspurified by silica gel column chromatography using 30% ethyl acetate inpet ether to yield the title compound (1.22 g, 45%) as a white solid, mp228-230° C.

¹H NMR (CDCl₃): δ 0.98 (t, J=7.3 Hz, 3H), 1.01-1.25 (m, 4H), 1.72-1.99(m, 3H), 2.82 (t, J=7.6 Hz, 21), 4.23 (s, 3H), 11.05 (br s, 1H, D₂Oexchangeable).

Preparation 13

Ethyl 2-(4-nitrophenoxy)pentanoate

To a solution of 4-nitrophenol (11.08 g, 79.7 mmol) inN,N-dimethylformamide (70 mL) anhydrous K₂CO₃ (28.1 g, 203.8 mmol) wasadded and stirred for 30 min at room temperature. Ethyl2-bromopentanoate obtained in preparation 1 (20.0 g, 95.7 mmol) inN,N-dimethylformamide (25 mL) was added to the above reaction mixturewith vigorous stirring. The stirring was continued at room temperaturefor further 18 h. The reaction mixture was diluted with ethyl acetate(400 mL) and washed the organic layer successively with water (3×300mL)_(y) and brine, dried over anhydrous sodium sulfate and concentratedto afford the title compound (23.0 g, 92%) as a gummy mass.

¹H NMR (CDCl₃): δ 0.99 (t, J=7.6 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H),1.42-1.64 (m, 2H), 1.92-2.04 (m, 2H), 4.22 (q, J=7.2 Hz, 2H), 4.71 (t,J=6.1 Hz, 1H), 6.92 (d, J=9.3 Hz, 2H), 8.18 (d, J=9.3 Hz, 2H).

Preparation 14

Ethyl 2-(4-aminophenoxy)pentanoate

To a solution of ethyl 2-4-nitrophenoxy)pentanoate obtained inpreparation 13 (22.5 g, 84.3 mmol) in dioxane (65 mL), 10% Pd—C (5.63 g)was added and hydrogenated by passing hydrogen gas at 40 psi at roomtemperature for 5 h. The reaction mixture was filtered through celitebed and washed with dioxane. The filtrate and washings were combined,concentrated, and purified by silica gel column chromatography using 20%ethyl acetate in pet ether as eluent to yield the title compound (14.0g, 70%).

¹H NMR (CDCl₃): δ 0.94 (t, J=7.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H),1.40-1.62 (m, 2H), 1.78-1.96 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 4.45 (t,J=6.3 Hz, 1H), 6.5 (d, J=6.8 Hz, 2H), 6.73 (d, J=6.3 Hz, 2H).

Preparation 15

Ethyl 6-[4-(1-ethoxycarbonylbutoxy)amino]hexanoate

The title compound (1.55 g, 48.5%) was obtained as a liquid from ethyl2-4-aminophenoxy)pentanoate (2.0 g, 8.4 mmol) obtained in preparation 14by reacting with ethyl 6-bromohexanoate (2.26 g, 10.1 mmol) usinganhydrous potassium carbonate (3.5 g, 25.31 mmol) at room temperaturefor 48 h by following the similar procedure as described in preparation13.

¹H NMR (CDCl₃): δ 0.97 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.3 Hz, 611),1.36-1.76 (m, 8H), 1.80-1.96 (m, 2H), 2.31 (t, I=7.3 Hz, 2H), 3.06 (t,I=6.8 Hz, 2H), 4.07-4.26 (m, 4H), 4.46 (t, J=6.4 Hz, 1H), 6.52 (d, J=6.8Hz, 2H), 6.77 (d, J=6.3 Hz, 2H).

Preparation 16

Ethyl6-chloromethyl[4-(1-ethoxycarbonylbutoxy)phenyl]carboxamido-hexanoate

The title compound (1.45 g, 78%) was obtained from ethyl6-[4-(1-ethoxycarbonylbutoxy)anilino]hexanoate (1.55 g, 4.1 mmol)obtained in preparation 15 by reacting with chloroacetyl chloride (0.47mL, 6.13 mmol) using dichloromethane (18 mL) in presence of triethylamine (1.7 mL, 12.27 mmol) at room temperature for 16 h by following thesimilar procedure as described in preparation 4.

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H),1.25-1.41 (m, 3H), 1.40-1.70 (m, 8H), 1.86-2.09 (m, 2H), 2.27 (t, J=7.6Hz, 2H), 3.66 (t, J=7.3 Hz, 2H), 3.78 (s, 2H), 4.11 (q, J=7.1 Hz, 2H),4.25 (q, J=6.8 Hz, 2H), 4.61 (t, J=6.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H),7.10 (d, J=8.8 Hz, 2H).

Preparation 17

Ethyl 2-ethoxy-3-[4-nitrophenyl]propeonate

To an ice-cold slurry of sodium hydride (60% oil coated, 5.3 g, 132.5mmol), a solution of the Wittig salt (triethyl 2-ethoxyphosphonoacetate)(23.16 g, 86.1 mmol), (prepared as disclosed in our U.S. Pat. No.6,054,453), in THF (150 mL) was slowly added drop wise with vigorousstirring. The reaction temperature was brought to room temperature andheated until the reaction mixture became clear. The reaction mixture wascooled to 0° C. and a solution of p-nitrobenzaldehyde (10.0 g, 66.2mmol) in THF (150 mL) was added drop wise and stirred at roomtemperature for overnight THF was then removed and the residue was takenin ethyl acetate, and washed successively with water and brine, driedover anhydrous sodium sulfate and concentrated. The residue waschromatographed using 5% ethyl acetate in pet ether to afford the titlecompound as E and Z isomers (15.1 g, 86%) as bright yellow liquid.

Z isomer. ¹H NMR (CDCl₃): δ 1.16 (t, J=7.2 Hz, 3H), 1.46 (t, J=7.0 Hz,3H), 3.99 (q, J=7.0 Hz, 2H), 4.19 (q, J=7.1 Hz, 21), 6.04 (s, 1H), 7.34(d, J=8.7 Hz, 2H), 8.15 (d, J=8.6 Hz, 2H).

E isomer. ¹H NMR (CDCl₃): δ 1.35-1.47 (m, 6H), 4.12 (q, J=7.0 Hz, 2H),4.34 (q, J=7.2 Hz, 2H), 6.92 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 8.22 (d,J=8.7 Hz, 2H).

Preparation 18

Ethyl 2-ethoxy-3-[4-aminophenyl]propanoate

The title compound (3.2 g, 55%) was synthesized by hydrogenating ethyl2-ethoxy-3-[4-nitrophenyl]propeonate obtained in preparation 17 (6.5 g,24.4 mmol) by passing hydrogen gas at 60 psi, taken in dioxane (65 mL),in presence of 10% Pd—C (2.6 g) at room temperature for 36 h byfollowing the same procedure as described in preparation 14.

¹H NMR (CDCl₃): δ 1.17 (t, J=6.1 Hz, 3H), 1.23 (t, J=6.1 Hz, 3H), 2.91(d, J=6.7 Hz, 2H), 3.28-3.44 (m, 1H), 3.52-3.68 (m, 1H), 3.95 (t, 3=6.8Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 6.62 (d, J=8.1 Hz, 2H), 7.04 (d, J=8.2Hz, 2H).

Preparation 19

Ethyl 2-ethoxy-3-[4-(4-fluorobenzylamino)phenyl]propanoate

The title compound (100 mg, 14%) was obtained as yellow colored liquidfrom ethyl 2-ethoxy-3-[4-aminophenyl]propanoate (500 mg, 2.11 mmol)obtained in preparation 18, 1-bromomethyl-4-fluorobenzene (438 mg, 2.32mmol) and anhydrous potassium carbonate (873 mg, 6.33 mmol) at roomtemperature for 18 h by following the similar procedure as described inpreparation 13.

¹H NMR (CDCl₃): δ 1.16 (t, J=6.9 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H), 2.89(d, J=6.8 Hz, 2H), 3.28-3.43 (m, 1H), 3.50-3.66 (m, 1H), 3.94 (t, J=6.6Hz, 1H), 4.15 (q, J=7.3 Hz, 2H), 4.27 (s, 2H), 6.54 (d, J=8.3 Hz, 2H),6.94-7.09 (m, 4H), 7.32 (dd, J=8.3 and 5.4 Hz, 2H).

Preparation 20

Ethyl3-[4-chloromethyl(4-fluorobenzyl)carboxamidophenyl]-2-ethoxypropanoate

The title compound (355 mg, 74%) was obtained as straw yellow coloredliquid from ethyl 2-ethoxy-3-[4-(4-fluorobenzylamino)phenyl]propanoate(390 mg, 1.13 mmol) obtained in preparation 19, chloroacetyl chloride(0.09 mL, 1.36 mmol) and dichloromethane in presence of triethyl amine(0.39 mL, 2.83 mmol) at room temperature for 16 h by following thesimilar procedure as described in preparation 4.

¹H NMR (CDCl₃): δ 1.14 (t, J=6.9 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H),2.95-3.06 (m, 2H), 3.25-3.42 (m, 1H), 3.55-3.70 (m, 1H), 3.83 (s, 2H),3.94 (dd, J=7.6 and 5.6 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 4.84 (s, 2H),6.80-7.00 (m, 4H), 7.15 (dd, J=8.3 and 5.9 Hz, 2H), 7.25 (d, J=8.3 Hz,2H).

Preparation 21

Ethyl 2-[4-{4-(4-ethoxycarbonylphenyl)butylamino}phenoxy]pentanoate

The title compound (1.35 g, 36.4%) was obtained as a liquid from ethyl2-(4-aminophenoxy)pentanoate (2.0 g, 8.4 mmol), obtained in preparation14, by reacting with ethyl 4-(4-bromobutyl)benzoate (2.65 g, 9.82 mmol)using anhydrous potassium carbonate (3.5 g, 25.31 mmol) at roomtemperature for 60 h following a similar procedure as described in thepreparation 13.

¹H NMR (CDCl₃): δ 0.97 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.39(t, J=7.3 Hz, 3H), 1.40-1.96 (m, 8H), 2.71 (t, J=7.1 Hz, 2H), 3.08 (t,J=6.6 Hz, 2H), 4.20 (t, J=7.1 Hz, 2H), 4.37 (q, J=7.5 Hz, 2H), 4.47 (t,J=7.1 Hz, 1H), 6.52 (d, J=8.8 Hz, 2H1), 6.77 (d, J=8.8 Hz, 2H), 7.25 (d,J=8.3 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H).

Preparation 22

Ethyl2-[4-chloromethyl{4-(4-ethyloxycarbonylphenyl)butyl}carboxamido-phenoxy]pentanoate

The title compound (1.4 g, 88%) was obtained from ethyl2-[4-{4-(4-ethoxycarbonylphenyl)butylamino}phenoxy]pentanoate (1.35 g,3.07 mmol), obtained in preparation 21, by reacting with chloroacetylchloride (0.28 mL, 3.68 mmol) using dichloromethane (20 mL) in presenceof triethyl amine (1.08 mL, 7.67 mmol) at room temperature for 40 h byfollowing the similar procedure as described in preparation 4.

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 311), 1.24 (t, J=7.3 Hz, 3H), 1.38(t, J=7.3 Hz, 3H), 1.48-1.70 (m, 6H), 1.82-2.05 (m, 2H), 2.66 (t, J=6.8Hz, 2H), 3.68 (t, J=6.8 Hz, 2H), 3.77 (s, 2H), 4.24 (t, J=7.0 Hz, 211),4.36 (q, J=7.1 Hz, 2H), 4.60 (t, J=6.1 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H),7.05 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 7.93 (d, J=7.8 Hz, 2H).

Preparation 23

5-Ethyl-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-]pyrimidin-7-one

To 4-amino-1-methyl-3-propyl-1H-5-pyrazole carboxamide obtained in stepvi. preparation 10 (1.3 g, 7.1 mmol) in xylene (10.5 mL), propionic acid(10.5 mL) was added and cooled in ice bath. Triethyl amine (2.2 mL, 15.7mmol) was added to the reaction mixture and stirred for 15 min.Propionyl chloride was added and stirred at the same temperature for 30min. The reaction mixture was refluxed for 36 h and the solvent wasremoved under vacuum. The resulting residue was diluted with water andextracted with ethyl acetate (3×10 mL). The combined organic extractswere washed with water, brine, dried (Na₂SO₄) and concentrated. Thecrude compound was purified by silica gel column chromatography using30% ethyl acetate in pet. ether as eluent to yield the title compound(560 mg, 36%).

¹H NMR (CDCl₃): δ 11.1 (broad s, D₂O exchangeable, 1H), 4.23 (s, 3H),2.89-2.69 (m, 4H), 1.85-1.71 (m, 2H), 1.37 (t, J=7.50 Hz, 3H), 0.98 (t,J=7.40 Hz, 3H).

Preparation 24.

1,5-Dimethyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one

The title compound (360 mg, 36%) was obtained as fluffy solid from4-amino-1-methyl-3-propyl-1H-5-pyrazole carboxamide (950 mg, 5.2 mmol)obtained in step vi preparation 10, acetyl chloride (450 mg, 5.74 mmol),triethyl amine (1.15 g, 11.48 mmol) and acetic acid (7.5 mL) byrefluxing in xylene (7.5 mL) for 72 h following a similar procedure asdescribed in preparation 23.

¹H NMR (CDCl₃): δ 11.18 (broad s, D₂O exchangeable, 1H), 4.23 (s, 3H),2.84 (t, J=7.60 Hz, 2H), 2.51 (s, 3H), 1.84-1.75 (m, 2H), 0.98 (t,J=7.30 Hz, 3H).

EXAMPLE 1 Ethyl 2-[4-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl(heptyl)carboxamido)phenylsulfanyl]pentanoate

A mixture of5-ethyl-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-7-oneobtained in preparation 23 (236 mg, 1.07 mmol) and anhydrous K₂CO₃ (444mg, 3.21 mmol) in dry N,N-dimethylformamide (4 mL) was stirred underargon atmosphere for 30 mm at room temperature. Ethyl2-[4-chloromethyl(heptyl)carboxamidophenylsulfanyl]-pentanoate (597 mg,1.39 mmol), obtained in preparation 4, dissolved in dryN,N-dimethylformamide (3 mL) was added drop wise to the above reactionmixture at 0° C. The reaction mixture was stirred at room temperaturefor 48 h. The reaction mixture was diluted with ethyl acetate (25 mL),washed with water (3×15 mL), brine (20 mL), dried (Na₂SO₄) andconcentrated. The residue was column chromatographed using 10% ethylacetate in pet ether to afford the title compound (527 mg, 81%).

¹H NMR (CDCl₃): δ 0.85 (t, J=6.4 Hz, 3H), 0.96 (t J=7.6 Hz, 3H), 0.99(t, J=7.6 Hz, 3H), 1.15-1.62 (m, 20H), 1.70-1.90 (m, 2H), 2.84-3.00 (m,4H), 3.63-3.79 (m, 3H), 4.10-4.22 (m, 5H), 4.82 (s, 2H), 7.26 (d, 3=8.3Hz, 2H), 7.54 (d, J=8.3 Hz, 2H).

EXAMPLE 22-[4-(5-Ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl-(heptyl)carboxamido)phenylsulfanyl]pentanoicAcid

To a solution of ethyl2-[4-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl(heptyl)carboxamido)phenylsulfanyl]pentanoate(527 mg, 0.86 mmol), obtained in example 1, in methanol (5 mL) sodiumcarbonate (457 mg, 4.31 mmol) in water (5 mL) was added and stirred atroom temperature for 12 h. Methanol was removed from the reactionmixture under reduced pressure and the resulting aqueous layer wasacidified with 2N HCl at 0° C. to pH-2. The aqueous layer was extractedwith ethyl acetate, dried (Na₂SO₄) and concentrated. The residue waschromatographed using 60% ethyl acetate in pet ether as eluent to affordthe title compound (27 mg, 5.4%), mp 84-86° C.

¹H NMR (CDCl₃): δ 0.87 (t, J=6.4 Hz, 3H), 1.01 (t, J=7.3 Hz, 6H),1.20-1.42 (m, 11H), 1.45-1.68 (m, 3H), 1.74-1.95 (m, 21), 2.84-3.00 (m,6H), 3.63-3.84 (m, 4H), 4.15 (s, 3H), 4.79 (s, 21), 7.27 (d, J=8.8 Hz,2H), 7.59 (d, J=8.3 Hz, 2H).

EXAMPLE 3 Ethyl2(S)-2-ethoxy-3-[4-{2-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoate

A mixture of5-ethyl-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-7-oneobtained in preparation 23 (40.0 g, 180 mmol) and anhydrous K₂CO₃ (75.2g, 544 mmol) in dry N,N-dimethylformamide (200 mL) was stirred underargon atmosphere for 30 min at room temperature.Ethyl(2S)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (3.9 g, 11.3mmol), obtained in preparation 5, dissolved in dry N,N-dimethylformamide(7 mL) was added drop wise to the above mixture at room temperature. Thereaction mixture was stirred at room temperature for 24 h. The reactionmixture was diluted with ethyl acetate (1 L), washed with water (3×400mL), brine (200 mL), dried (Na₂SO₄) and concentrated. The residue wascolumn chromatographed using 10% ethyl acetate in pet ether to affordthe title compound (14.36 g, 16.4%), mp 59-60° C.

[α]_(D) ²=−11.0° (c=1.0, CH₃OH).

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 3H), 1.17 (t, I=6.6 Hz, 3H), 1.23(t, J=6.8 Hz, 3H), 1.36 (t, J=7.3 Hz, 3H), 1.74-1.93 (m, 2H), 2.87-3.03(m, 6H), 3.26-3.47 (m, 1H), 3.51-3.88 (m, 1H), 3.97 (t, J=6.6 Hz, 1H),4.14 (s, 3H), 4.16 (q, J=7.3 Hz, 2H), 4.38 (t, J=4.7 Hz, 2H), 4.91 (t,J=4.7 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H).

EXAMPLE 4 Methyl2(S)-2-ethoxy-3-[4-{2-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-7-yloxy)ethoxy}phenyl]propanoate (A) &2(S)-2-Ethoxy-3-[4-{2-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoicAcid (B)

To a solution of ethyl2(8)-2-ethoxy-3-[4-{2-5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoate(5.0 g, 10.33 mmol), obtained in example 3, in methanol (250 mL) sodiumcarbonate (5.47 g, 51.65 mmol) in water (25 mL) was added and stirred atroom temperature for 24 h Methanol was removed from the reaction mixtureunder vacuum and the resulting aqueous layer was extracted with ethylacetate which was washed with water, brine, dried (Na₇SO₄) andconcentrated to get a trans esterified product i.e., the correspondingmethyl ester (4A) of the free acid (1.44 g, 29.7%), mp 68-70° C. Theaqueous layer was acidified with 2N HCl at low temperature to pH˜2. Thesolids were filtered and washed with cold water, dried under vacuumovernight to yield the title compound (4B) (2.9 g, 59.9%), mp 138-140°C.

4A: [α]_(D) ²⁵=−9.0° (c=0.5, CH₃OH).

¹H NMR (CDCl₃): δ 1.01 (t, J=7.3 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.23(t, J=7.6 Hz, 3H), 1.77-1.95 (m, 2H), 2.87-3.03 (m, 6H), 3.27-3.43 (m,1H), 3.54-3.69 (m, 1H), 3.72 (s, 3H), 4.01 (t, J=6.6 Hz, 1H), 4.16 (s,3H), 4.40 (t, J=4.7 Hz, 2H), 4.92 (t, J=4.7 Hz, 2H), 6.88 (d, J=8.3 Hz,2H), 7.17 (d, J=8.3 Hz, 2H).

4B: [α]_(D) ²⁵=−18.6° (c=0.5, CH₃OH).

¹H NMR (CDCl₃): δ 0.99 (t, I=7.3 Hz, 311), 1.18 (t, J=6.8 Hz, 3H), 1.36(t, J=7.6 Hz, 3H), 1.77-1.95 (m, 2H), 2.82-3.16 (m, 6H), 3.40-3.65 (m,2H), 4.00-4.12 (m, 1H), 4.14 (s, 3H), 4.39 (t, J=4.4 Hz, 2H), 4.92 (t,J=4.7 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 7.18 (d; J=8.8 Hz, 2H).

EXAMPLE 5 Ethyl2(S)-3-[4-{2-1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-dipyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoate

Method A: The title compound (2.26 g, 15%) was obtained as white solidby condensing1,5-dimethyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one(prepared as disclosed in our U.S. application Ser. No. 09/507,373) (6.6g, 32 mmol) with ethyl(2S)-3-[4-2-bromoethoxy)phenyl]-2-ethoxypropanoate(3.9 g, 11.3 mmol), obtained in preparation 5, in dryN,N-dimethylformamide (80 mL) in the presence of anhydrous K₂CO₃ (11.05g, 80.1 mmol) at room temperature by following the similar procedure asdescribed in example 3, mp 84-86° C.

Method B: To a cooled solution of triphenyl phosphine (1.78 g, 6.8 mmol)in dry THF (5 mL) DIAD (1.35 mL, 6.8 mmol) was added drop wise andstirred for 15 min.1,5-Dimethyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (0.7g, 3.4 mmol) in THF (25 mL) was added drop wise to the above reactionmixture at 0° C. The reaction mixture was stirred for 10 min at roomtemperature. The reaction mixture was cooled and a solution ofethyl(2S)-2-ethoxy-3-[4-2-hydroxyethoxy)phenyl]propanoate (1.054 g, 3.79mmol), obtained in preparation 9, in THF (10 mL) was added to thereaction mixture slowly. The reaction mixture was allowed to stir atroom temperature for 3 days. THF was removed under reduced pressure andthe residue was purified by column chromatography using 15% ethylacetate in pet ether to get the title compound (0.8 g, 50%).

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 3H), 1.17 (t, J=6.8 Hz, 3H), 1.23(t, J=6.8 Hz, 3H), 1.72-1.84 (m, 2H), 2.70 (s, 3H), 2.92-3.02 (m, 4H),3.25-3.42 (m, 1H), 3.52-3.70 (m, 1H), 3.97 (t, J=6.6 Hz, 1H), 4.15 (s,3H), 4.17 (q, J=6.6 Hz, 2H), 4.39 (t, J=4.7 Hz, 2H), 4.91 (t, 3=4.4 Hz,2H), 6.87 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H).

EXAMPLE 62(S)-3-[4-{2(1,5-Dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoicAcid

The title compound (0.3 g, 40%) was obtained as white solid from ethyl2(S)-3-[4-{2-(1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}-phenyl]-2-ethoxypropanoate(0.8 g, 1.7 mmol) obtained in example 5 by hydrolyzing in methanol-water(2:1, 30 mL) using sodium carbonate (0.9 g, 8.5 mmol) at roomtemperature for 48 h following a similar procedure as described inexample 2, mp 148-150° C.

[α]_(D) ²⁵=−7.6° (c=0.5, CHCl₃).

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H),1.75-1.93 (m, 2H), 2.69 (s, 3H), 2.17-3.10 (m, 4H), 3.45-3.65 (m, 2H),4.06 (dd, J=7.0 and 4.7 Hz, 1H), 4.14 (s, 3H), 4.39 (t, J=4.6 Hz, 2H),4.91 (t, J=5.1 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H).

EXAMPLE 7 Ethyl2-ethoxy-3-[4-{2-(1-methyl-5-phenyl-3-propyl-1H-pyrazolo-[4,3-d]-pyrimidin-7-yloxy)ethoxy}phenyl]propanoate

The title compound (480 mg, 96.7%) was obtained as white solid bycondensing1-methyl-5-phenyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one,obtained in preparation 11, (250 mg, 0.93 mmol) with ethyl3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate obtained in step ii.Preparation 6 (386 mg, 1.12 mmol) was taken in dry N,N-dimethylformamide(10 mL) in the presence of anhydrous K₂CO₃ (386 mg, 2.79 mmol) at roomtemperature for 12 h following the similar procedure as described inexample 1, mp 80-82° C.

¹H NMR (CDCl₃): δ 1.04 (t, J=7.3 Hz, 3H1), 1.17 (t, J=7.1 Hz, 3H), 1.23(t, J=6.8 Hz, 3H), 1.84-2.01 (m, 2H), 2.92-3.09 (m, 4H), 3.28-3.44 (m,1H), 3.52-3.70 (m, 1H), 3.97 (t, J=6.6 Hz, 1), 4.17 (q, J=7.1 Hz, 2H),4.19 (s, 3H), 4.45 (t, J=4.7 Hz, 2H), 5.05 (t, J=4.6 Hz, 2H), 6.88 (d,J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.40-7.55 (m, 3H), 8.42-8.55 (m,2H).

EXAMPLE 83-[4-{2-(1-Methyl-5-phenyl-3-propyl-1H-pyrazolo-14,3-d]pyrimidin-7-yloxy)ethoxy}phenyl-2-ethoxypropanoicAcid

The title compound (149 mg, 63%) obtained as a white solid from ethyl2-ethoxy-3-[4-{2-(1-methyl-5-phenyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-7-yloxy)-ethoxy}phenyl]propanoate(253 mg, 0.47 mmol) obtained in example 7 by hydrolyzing inmethanol-water (3:2, 8 mL) using sodium carbonate (252 mg, 2.37 mmol) atroom temperature for 24 h following the similar procedure as describedin example 2, mp 124-126° C.

¹H NMR (CDCl₃): δ 1.04 (t, J=7.3 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H),1.84-2.01 (m, 2H), 2.92-3.17 (m, 4H), 3.42-3.69 (m, 2H), 4.06 (t, J=5.6Hz, 1H), 4.19 (s, 3H), 4.47 (t, J=4.7 Hz, 2H), 5.06 (t, J=4.8 Hz, 2H),6.89 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.39-7.56 (m, 3H), 8.48(d, J=8.3 Hz, 2H).

EXAMPLE 9Ethyl(2S)-3-[4-{2-(5-cyclopropyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoate

The title compound (230 g, 38%) was obtained by condensing1-methyl-3-propyl-5-cyclopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-one (200mg, 0.86 mmol) obtained in preparation 12 withethyl(2S)-3-[4-2-bromoethoxy)phenyl]-2-ethoxypropanoate (357 mg, 1.03mmol) obtained in preparation 5 in dry N,N-dimethylformamide (8 mL) inthe presence of anhydrous K₂CO₃ (357 mg, 2.58 mmol) at room temperaturefor 24 h following the similar procedure as described in example 3.

¹H NMR (CDCl₃): δ 1.01 (t, J=7.3 Hz, 3H), 1.05-1.31 (m, 10H), 1.71-1.93(m, 2H), 2.17-2.31 (m, 1H), 2.87-3.05 (m, 4H), 3.28-3.43 (m, 1H),3.51-3.68 (m, 1H), 3.97 (t, J=7.3 Hz, 1H), 4.12 (s, 3H), 4.17 (q, J=7.1Hz, 21), 4.36 (t, J=4.4 Hz, 2H), 4.83 (t, J=4.4 Hz, 2H), 6.86 (d, J=8.3Hz, 2H), 7.17 (d, J=8.3 Hz, 2H).

EXAMPLE 10(2S)-3-[4-{2-(5-Cyclopropyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoicAcid

The title compound (145 mg, 81%) was obtained as a white solid fromethyl(2S)-3-[4-{2-(5-cyclopropyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)-ethoxy]phenyl]-2-ethoxypropanoate(190 mg, 0.38 mmol) obtained in example 9 by hydrolyzing inmethanol-water (5:2, 7 mL) using sodium carbonate (203 mg, 1.9 mmol) atroom temperature for 18 h following the similar procedure as describedin example 2, mp 118-120° C.

[α]_(D) ²⁵=−14.0° (c=0.5, CH₃OH).

¹H NMR (CDCl₃): δ 0.93-1.13 (m, 7H), 1.18 (t, J=7.1 Hz, 3H), 1.72-1.93(m, 2H), 2.17-2.31 (m, 1H), 2.93 (t, J=7.6 Hz, 2H), 2.96-3.14 (m, 2H),3.40-3.68 (m, 2H), 4.02-4.08 (m, 1H), 4.10 (s, 3H), 4.35 (t, J=4.6 Hz,2H), 4.83 (t, J=4.6 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.3 Hz,2H).

EXAMPLE 11 Ethyl6-[5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl{4-(1-ethyloxycarbonylbutoxy)phenyl}carboxamido]hexanoate

The title compound (400 mg, 55%) was obtained by condensing5-ethyl-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-7-oneobtained in preparation 23 (250 mg, 1.14 mmol) with ethyl6-chloromethyl[4-(1-ethyloxycarbonylbutoxy)phenyl]carboxamidohexanoate,obtained in preparation 16, in dry N,N-dimethylformamide (10 mL) in thepresence of anhydrous K₂CO₃ (470 mg, 3.41 mmol) at room temperature for96 h following a similar procedure as described in example 1.

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 6H), 1.23 (t, J=7.1 Hz, 3H),1.24-1.38 (m, 10H), 1.43-1.70 (m, 4H), 1.75-2.00 (m, 4H), 2.26 (t, J=7.6Hz, 2H), 2.82-2.98 (m, 4H), 3.67 (t, J=7.3 Hz, 2H), 4.09 (q, J=7.2 Hz,2H), 4.17 (q, J=7.3 Hz, 2H), 4.19 (s, 3H), 4.63 (t, J=5.8 Hz, 1H), 4.81(s, 2H), 6.95 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H).

EXAMPLE 126-[4-(1-Carboxybutoxy)phenyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido]hexanoic Acid

The title compound (200 mg, 73%) was obtained from ethyl6-[5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl{4-(1-ethyloxycarbonyl-butoxy)phenyl}carboxamido]hexanoate(300 mg, 0.47 mmol), obtained in example 11, by hydrolyzing inmethanol-water using sodium carbonate (248 mg, 2.35 mmol) at roomtemperature for 18 h following a similar procedure as described inexample 2.

¹H NMR (CDCl₃): δ 0.98 (t, J=7.3 Hz, 31), 1.02 (t, J=7.3 Hz, 3H),1.22-1.42 (m, 7H), 1.43-1.88 (m, 6H), 1.92-2.11 (m, 2H), 2.31 (t, J=6.8Hz, 2H), 2.80-2.99 (m, 4H), 3.58-3.77 (m, 21), 4.17 (s, 31), 4.63 (t,J=5.9 Hz, 1H), 4.77 (d, I=5.2 Hz, 1H), 4.91 (d, J=4.8 Hz, 1H), 6.98 (d,J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H).

EXAMPLE 13 Bis-arginine Salt of6-[4-(1-carboxybutoxy)phenyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido]hexanoicAcid

To a solution of6-[4-(1-carboxybutoxy)phenyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido]hexanoicacid obtained in example 12 (72 mg, 0.123 mmol) in ethanol (2 mL) wasadded arginine (43 mg, 0.246 mmol) dissolved in ethanol (1 mL) andstirred the reaction mixture at room temperature for 18 h. Ethanol wasthen distilled off under vacuum, flushed with toluene (3×3 mL), driedunder high vacuum to yield the title compound as a hygroscopic solid(110 mg, 96%), mp 158-160° C.

¹H NMR (CD₃OD): δ 0.80-1,03 (m, 6H), 1.22-1.90 (m, 17H), 2.15 (t, J=6.8Hz, 2H), 2.83-2.99 (m, 2H), 3.10-3.37 (m, 8H), 3.41-3.75 (m, 6H), 4.16(s, 3H), 4.63-4.92 (m, 5H), 7.02 (d, J=8.8 Hz, 2H), 7.21 (d, I=9.2 Hz,2H).

EXAMPLE 14 3-[4-{2-(1,5-Dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoic Acid

To a cooled solution of triphenyl phosphine (420 mg, 1.6 mmol) in dryTHF (4 mL) DIAD (0.32 mL, 1.6 mmol) was added drop wise and stirred for15 min.1,5-Dimethyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (165mg, 0.8 mmol) in THF (6 mL) was added drop wise to the above reactionmixture at 0° C. The reaction mixture was stirred for 10 min at roomtemperature and cooled. To this ethyl2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propanoate (248 mg, 0.881 mmol),obtained in preparation 7, in THF (5 mL) was added slowly. The reactionmixture was allowed to stir at room temperature for 4 days. THF wasremoved under reduced pressure and the residue was purified by columnchromatography using 10% ethyl acetate in pet ether to get thecorresponding ester of the title compound.

To a solution of compound obtained above in methanol (4 mL) lithiumhydroxide (44 mg, 1.05 mmol) in water (1 mL) was added and stirred atroom temperature for 18 h. Methanol was removed from the reactionmixture under reduced pressure and the resulting aqueous layer wasacidified with 2N HCl at 0° C. to pH-2. The aqueous layer was extractedwith ethyl acetate, dried (Na₂SO₄) and concentrated. Columnchromatography of the residue, using 60% ethyl acetate in pet ether aseluent, afforded the title compound (50 mg), mp 142-144° C.

¹H NMR (CDCl₃): δ 0.98 (t, J=7.3 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H),1.73-1.92 (m, 2H), 2.68 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.98-3.15 (m,2H), 3.43-3.68 (m, 21), 4.06 (dd, J=7.1 and 4.7 Hz, 1H), 4.13 (s, 3H),4.37 (t, J=4.4 Hz, 2H), 4.90 (t, J=4.0 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H),7.17 (d, J=8.3 Hz, 2H).

EXAMPLE 153-[4-{2-(5-Ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoicAcid

The title compound (65 mg, 9%) was prepared from5-ethyl-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one(0.35 g, 1.6 mmol) following the similar procedure as described in theexample 14, mp 140-142° C.

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H), 1.37(t, J=7.6 Hz, 3H), 1.75-1.91 (m, 2H), 2.86-3.10 (m, 6H), 3.42-3.68 (m,2H), 4.06 (dd, J=7.3 and 4.4 Hz, 1H), 4.14 (s, 31), 4.40 (t, J=4.4 Hz,2H), 4.93 (t, J=4.9 Hz, 2H), 6.88 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.3 Hz,2H).

EXAMPLE 16 Ethyl3-[4-{1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl(4-fluorobenzyl)carboxamido}phenyl]-2-ethoxypropanoate

The title compound (170 mg, 47%) was obtained as white solid bycondensing1,5-dimethyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-oneobtained in preparation 24 (125 mg, 0.606 mmol) with ethyl3-[4-chloromethyl(4-fluorobenzyl)carboxamidophenyl]-2-ethoxypropanoateobtained in preparation 20 in dry N,N-dimethylformamide (7 mL) in thepresence of anhydrous K₂CO₃ (251 mg, 1.82 mmol) at room temperature for24 h following a similar procedure as described in example 1, mp 86-88°C.

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 3H), 1.15 (t, J=6.8 Hz, 3H), 1.23(t, J=7.1 Hz, 3H), 1.87-1.94 (m, 2H), 2.61 (s, 3H), 2.94 (t, J=7.5 Hz,2H), 3.00-3.09 (m, 2H), 3.30-3.44 (m, 1H), 3.55-3.73 (m, 1H), 3.97-4.27(m, 6H), 4.82 (s, 2H), 4.85 (s, 2H), 6.95 (t, J=8.5 Hz, 2H), 7.08 (d,J=8.3 Hz, 2H), 7.12-7.34 (m, 4H).

EXAMPLE 173-[4-{1,5-Dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl(4-fluorobenzyl)carboxamido}phenyl]-2-ethoxypropanoicAcid

The title compound (59 mg, 86%) obtained as white solid from Ethyl3-[4-{1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl(4-fluorobenzyl)carboxamido}phenyl]-2-ethoxypropanoate(72 mg, 122 μmol) obtained in example 16 by hydrolyzing inmethanol-water (3:1, 4 mL) using sodium carbonate (64 mg, 0.61 mmol) atroom temperature for 18 h by following a similar procedure as describedin example 2.

¹H NMR (CDCl₃): δ 0.99 (t, J=7.3 Hz, 3H), 1.15 (t, J=7.3 Hz, 3H),1.72-1.88 (m, 2H), 2.60 (s, 3H), 2.94 (t, J=7.1 Hz, 2H), 3.01-3.17 (m,2H), 3.35-3.73 (m, 2H), 4.03-4.21 (m, 4H), 4.78 (s, 2H), 4.86 (s, 2H),6.87 (d, J=8.3 Hz, 1H), 6.96 (t, J=8.8 Hz, 2H), 7.05-7.38 (m, 5H).

EXAMPLE 18 Ethyl2-(4-[5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-]pyrimidin-7-yloxy-methyl(4-(4-ethyloxycarbonylphenyl)butyl}carboxamido]phenoxy)pentanoate

The title compound (530 mg, 86%) was obtained by condensing5-ethyl-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-7-oneobtained in preparation 23 (193 mg, 0.88 mmol) with ethyl2-[4-chloromethyl{4-4-ethyloxycarbonylphenyl)butyl}carboxamidophenoxy]pentanoate (530 mg,1.03 mmol), obtained in preparation 22, in dry N,N-dimethylformamide (8mL) in the presence of anhydrous K₂CO₃ (358 mg, 2.59 mmol) at roomtemperature for 48 h following a similar procedure as described inexample 1.

¹H NMR (CDCl₃): δ 1.00 (t, J=7.3 Hz, 6H), 1.27 (t, J=7.1 Hz, 3H),1.32-1.44 (m, 6H), 1.47-1.72 (m, 6H), 1.77-2.02 (m, 4H), 2.65 (t, J=6.8Hz, 2H), 2.81-2.94 (m, 4H), 3.70 (t, J=6.4 Hz, 2H), 4.19 (s, 3H), 4.25(q, J=7.3 Hz, 2H), 4.36 (q, J=7.3 Hz, 2H), 4.62 (t, J=6.1 Hz, 1H), 4.80(s, 2H), 6.93 (d, 1=8.8 Hz, 2H), 7.17 (d, J=7.8 Hz, 2H), 7.19 (d, J=8.8Hz, 211), 7.92 (d, J=7.8 Hz, 2H).

EXAMPLE 192-[4-{4-(4-Carboxyphenyl)butyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido}phenoxy]pentanoic Acid

The title compound (81 mg, 88%) obtained as white solid from ethyl2-(4-[5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl{4-(4-ethyloxycarbonylphenyl)butyl}carboxamido]phenoxy)pentanoate (100mg, 142 μmol), obtained in example 18, by hydrolyzing in methanol-waterusing sodium carbonate (76 mg, 0.71 mmol) at room temperature for 18 hby following a similar procedure as described in example 2, mp0.178-180° C.

¹H NMR (CD₃OD+DMSO-d₆): δ 1.06-1.11 (m, 6H), 1.45 (t, J=7.5 Hz, 3H),1.62-2.18 (m, 10H), 2.74-3.12 (m, 61), 3.89 (t, J=5.4 Hz, 2H), 4.30 (s,31), 4.90 (br s, 1H), 5.06 (s, 2H), 7.16 (d, J=8.6 Hz, 2H), 7.36 (d,J=8.1 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 8.00 (d, J=8.1 Hz, 2H).

The compounds of the present invention lowered random blood sugar level,triglyceride, total cholesterol, LDL, VLDL and increased HDL. This wasdemonstrated by in vitro as well as in vivo animal experiments.

Demonstration of Efficacy of Compounds

A) In Vitro:

a) Determination of hPPARα Activity

Ligand binding domain of hPPARα was fused to DNA binding domain of Yeasttranscription factor GAL4 in eucaryotic expression vector. Usingsuperfect (Qiagen, Germany) as transfecting reagent HEK-293 cells weretransfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat different concentrations after 42 hrs of transfection and incubatedovernight. Luciferase activity as a function of compoundbinding/activation capacity of PPARα was measured using Packard Luclitekit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, PeterBroag and Melvyn Hollis. Gene 1992, 118: 137-141; Superfect TransfectionReagent Handbook. February 1997. Qiagen, Germany).

b) Determination of hPPARγ Activity

Ligand binding domain of hPPARγ1 was fused to DNA binding domain ofYeast transcription factor GAL4 in eucaryotic expression vector. Usinglipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cellswere transfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat 1 μM concentration after 48 hrs of transfection and incubatedovernight. Luciferase activity as a function of drug binding/activationcapacity of PPARγ1 was measured using Packard Luclite kit (Packard, USA)in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag andMelvyn Hollis. Gene 1992, 118: 137-141; Guide to EukaryoticTransfections with Cationic Lipid Reagents. Life Technologies, GIBCOBRL, USA). Example No. Concentration PPARα PPARγ Concentration 2  50 μM2.7 1 μM 1.4 4b 50 μM 5.1 1 μM 6.9

c) Determination of HMG CoA Reductase Inhibition Activity

Liver microsome bound reductase was prepared from 2% cholestyramine fedrats at mid-dark cycle. Spectrophotometric assays were carried out in100 mM KH₂PO₄, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg ofliver microsomal enzyme. Total reaction mixture volume was kept as 1 ml.Reaction was started by addition of HMG CoA. Reaction mixture wasincubated at 37° C. for 30 min and decrease in absorbance at 340 nm wasrecorded. Reaction mixture without substrate was used as blank(Goldstein, J. L and Brown, M. S. Progress in understanding the LDLreceptor and HMG CoA reductase, two membrane proteins that regulate theplasma cholesterol J. Lipid Res 1984, 25: 1450-1461). The test compoundsinhibited the HMG CoA reductase enzyme.

B) In Vivo

a) Efficacy in Genetic Models

Mutation in colonies of laboratory animals and different sensitivitiesto dietary regimens have made the development of animal models withnon-insulin dependent diabetes and hyperlipidemia associated withobesity and insulin resistance possible. Genetic models such as db/dband ob/ob (Diabetes, (1982) 31(1): 1-6) mice and zucker fa/fa rats havebeen developed by the various laboratories for understanding thepathophysiology of disease and testing the efficacy of new antidiabeticcompounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab.(1994). 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db micedeveloped by Jackson Laboratory, US, are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled. The state of pancreas andits course vary according to the models. Since this model resembles thatof type II diabetes mellitus, the compounds of the present inventionwere tested for blood sugar and triglycerides lowering activities.

Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight rangeof 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animalhouse, were used in the experiment The mice were provided with standardfeed (National Institute of Nutrition (NIN), Hyderabad, India) andacidified water, ad libitum. The animals having more tan 350 mg/dl bloodsugar were used for testing. The number of animals in each group was 4.

Test compounds were suspended on 0.25% carboxymethyl cellulose andadministered to test group at a dose of 0.1 mg to 30 mg/kg through oralgavage daily for 6 days. The control group received vehicle (dose 10ml/kg). On 6th day the blood samples were collected one hour afteradministration of test compounds/vehicle for assessing the biologicalactivity.

The random blood sugar and triglyceride levels were measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma. The plasma glucose and triglyceride levels were measuredspectrometrically, by glucose oxidase and glycerol-3-PO₄oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively.

The blood sugar and triglycerides lowering activities of the testcompound was calculated according to the formula.

No adverse effects were observed for any of the mentioned compounds ofinvention in the above test. Dose (mg/ Reduction in Blood TriglycerideCompound kg) Glucose Level (%) Lowering (%) Example 4a 10 48 69 Example4b 10 56 17 Example 5 3 61 51

The ob/ob mice were obtained at 5 weeks of age from Bomholtgard, Denmarkand were used at 8 weeks of age. Zucker fa/fa fatty rats were obtainedfrom IffaCredo, France at 10 weeks of age and were used at 13 weeks ofage. The animals were maintained under 12 hour light and dark cycle at25±1° C. Animals were given standard laboratory chow (NIN, Hyderabad,India) and water, ad libitum (Fujiwara, T., Yoshioka, S., Yoshioka, T.,Ushiyama, I and Honikoshi, H. Characterization of new oral antidiabeticagent CSO-045. Studies in KK and ob/ob mice and Zucker fatty rats.Diabetes 1988, 37: 1549-1558).

The test compounds were administered at 0.1 to 30 mg/kg/day dose for 9days. The control animals received the vehicle (0.25%carboxymethylcellulose, dose 10 ml/kg) through oral gavage.

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 9 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride, glucose, free fatty acid, total cholesterol and insulinestimations. Measurement of plasma triglyceride, glucose, totalcholesterol were done using commercial kits (Dr. Reddy's Laboratory,Diagnostic Division, India). The plasma free fatty acid was measuredusing a commercial kit from Boehringer Mannheim, Germany. The plasmainsulin was measured using a RIA kit (BARC, India). The reduction ofvarious parameters examined are calculated according to the formulagiven below.

In ob/ob mice oral glucose tolerance test was performed after 9 daystreatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg ofglucose orally. The blood samples were collected at 0, 15, 30, 60 and120 min for estimation of plasma glucose levels.

The experimental results from the db/db mice, ob/ob mice, Zucker fa/farats suggest that the novel compounds of the present invention alsopossess therapeutic utility as a prophylactic or regular treatment fordiabetes, obesity, cardiovascular disorders such as hypertension,hyperlipidaemia and other diseases; as it is known from the literaturethat such diseases are interrelated to each other.

Blood glucose level and triglycerides are also lowered at doses greaterthan 10 mg/kg. Normally, the quantum of reduction is dose dependent andplateaus at certain dose.

b) Plasma Triglyceride and Cholesterol Lowering Activity inHypercholesterolemic Rat Models

Male Sprague Dawley rats (NIN stock) were bred in DRF animal house.Animals were maintained under 12 hour light and dark cycle at 25±1° C.Rats of 180-200 gram body weight range were used for the experimentAnimals were made hypercholesterolemic by feeding 2% cholesterol and 1%sodium cholate mixed with standard laboratory chow [National Instituteof Nutrition (NIN), Hyderabad, India] for 6 days. Throughout theexperimental period the animals were maintained on the same diet (Petit,D., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate onliver lipids and lipoprotein synthesis in normal and hyperlipidemicrats. Atherosclerosis 1988, 74: 215-225).

The test compounds were administered orally at a dose 0.1 to 30mg/kg/day for 3 days. Control group was treated with vehicle alone(0.25% Carboxymethylcellulose; dose 10 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 3 day of compound treatment. The blood wascollected from the retro-orbital sinus through heparinised capillary inEDTA containing tubes. After centrifugation, plasma sample was separatedfor total cholesterol, HDL and triglyceride estimations. Measurement ofplasma triglyceride, total cholesterol and HDL were done usingcommercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).LDL and VLDL cholesterol were calculated from the data obtained fortotal cholesterol, HDL and triglyceride. The reduction of variousparameters examined are calculated according to the formula.

c) Plasma Triglyceride and Total Cholesterol Lowering Activity in SwissAlbino Mice and Guinea Pigs

Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NINand housed in DRF animal house. All these animals were maintained under12 hour light and dark cycle at 25±1° C. Animals were given standardlaboratory chow (NIN, Hyderabad, India) and water, ad libitum. SAM of20-25 g body weight range and Guinea pigs of 500-700 g body weight rangewere used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V.,Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil andnicotinic acid on plasma lipoprotein levels in normal and hyperlipidemicmice. Atherosclerosis. 1988. 70: 107-114).

The test compounds were administered orally to Swiss albino mice at 0.3to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle(0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds wereadministered orally to Guinea pigs at 0.3 to 30 mg/g/day dose for 6days. Control animals were treated with vehicle (0.25%Carboxymethylcellulose; dose 5 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 6 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride and total cholesterol (Wieland, O. Methods of Enzymaticanalysis. Bergermeyer, H. O., Ed., 1963. 211-214; Trinder, P. Ann. Clin.Biochem 1969, 6: 24-27). Measurement of plasma triglyceride, totalcholesterol and HDL were done using commercial kits (Dr. Reddy'sDiagnostic Division, Hyderabad, India). Compound Dose (mg/kg)Triglyceride Lowering (%) 8 10 61 7 3 43 10 3 42

c) Body Weight Reducing Effect in Cholesterol Fed Hamsters

Male Syrian Hamsters were procured from NIN, Hyderabad, India. Animalswere housed at DRF animal house under 12 hour light and dark cycle at25±1° C. with free access to food and water. Animals were maintainedwith 1% cholesterol containing standard laboratory chow (NIN) from theday of treatment.

The test compounds were administered orally at 1 to 30 mg/kg/day dosefor 15 days. Control group animals were treated with vehicle (Mill Qwater, dose 10 ml/kg/day). Body weights were measured on every 3^(rd)day.

Formulae for Calculation:

-   1. Percent reduction in Blood sugar/triglycerides/total cholesterol    were calculated according to the formula:    ${{Percent}\quad{reduction}\quad(\%)} = {\left\lbrack {1 - \frac{{TT}/{OT}}{{TC}/{OC}}} \right\rbrack \times 100}$-   OC=Zero day control group value-   OT=Zero day treated group value-   TC=Test day control group value-   TT=Test day treated group value-   2. LDL and VLDL cholesterol levels were calculated according to the    formula: $\begin{matrix}    {{{LDL}\quad\text{cholesterol}\quad{in}\quad{mg}\text{/dl}} = \left\lbrack {{\text{Total}\quad\text{cholesterol}} -} \right.} \\    {{{HDL}\quad\text{cholesterol}} -} \\    {\left. \frac{\text{Triglyceride}}{5} \right\rbrack\quad{mg}\text{/dl}}    \end{matrix}$ $\begin{matrix}    {{{VLDL}\quad\text{cholesterol}\quad{in}\quad{mg}\text{/dl}} = \left\lbrack {{\text{Total}\quad\text{cholesterol}} -} \right.} \\    {{{HDL}\quad\text{cholesterol}} -} \\    {\left. {{LDL}\quad\text{cholesterol}} \right\rbrack\quad{mg}{\text{/dl}.}}    \end{matrix}$

1. Novel alkyl carboxylic acids of compound of the general formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, alkanoyl, acyl,substituted or unsubstituted aralkyl groups; R² represents hydrogen,hydroxy, halogen, substituted or unsubstituted groups selected fromalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy,aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonylgroups; R³ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togetherform a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which can optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Grepresents O or S; X represents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)O—, —(CH₂)NR⁵CO—; where R⁵ represents hydrogen or substitutedor unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, alkanoyloxy, aroyl, aralkanoyl,heterocyclyl, heteroaryl, heteroaralkyl groups or(C₁-C₁₂)alkylcarboxylic acid and its derivatives; Y represents O, S, NR⁶or CHR⁷; where R⁶ represents hydrogen or substituted or unsubstitutedgroups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; R⁷ represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R¹; m and p are integers ranging from 0-4; n is aninteger in the range of 1-4; A represents pyrazolopyrimidine orimidazolopyrimidine of the formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom are same or differentand represent hydrogen, halogen, hydroxy, nitro, cyano, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.
 2. A compoundaccording to claim 1, wherein when the groups represented by R² aresubstituted, the substituents are selected from halogen, hydroxy, nitroor unsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl,heteroaryl, heteroaralkyl, alkanoyl, alkanoyloxy, hydroxyalkyl, amino,alkanoylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl,alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups,carboxylic acid or its derivatives or sulfonic acid or its derivatives.3. A compound according to claims 1 to 2 wherein Ar representssubstituted or unsubstituted groups selected from divalent phenylene,naphthylene, pyrrolyl, pyridyl, quinolinyl, benzofuryl,dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl,indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl orbenzoxazolyl groups.
 4. A compound according to claim 1, which isselected from: Ethyl2-[4-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl(heptyl)carboxamido)phenylsulfanyl]pentanoateor its salts in its single enantiomeric form or as a racemate;2-[4-(5-Ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl-(heptyl)carboxamido)phenylsulfanyl]pentanoicacid or its salts in its single enantiomeric form or as a racemate;Ethyl2-ethoxy-3-[4-{2-(S-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoateor its salts in its single enantiomeric form or as a racemate; Methyl2-ethoxy-3-[4-{2-(5-thyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-7-yloxyethoxy}phenyl]propanoateor its salts in its single enantiomeric form or as a racemate;2-Ethoxy-3-[4-{2-(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoicacid or its salts in its single enantiomeric form or as a racemate;Ethyl3-[4-{2-(1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoateor its salts in its single enantiomeric form or as a racemate;3-[4-{2-(1,5-Dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)-ethoxy}phenyl]-2-ethoxypropanoicacid or its salts in its single enantiomeric form or as a racemate;Ethyl2-ethoxy-3-[4-{2-(1-methyl-5-phenyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]propanoateor its salts in its single enantiomeric form or as a racemate;3-[4-{2-(1-Methyl-5-phenyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoicacid or its salts in its single enantiomeric form or as a racemate;Ethyl3-[4-{2-(5-cyclopropyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoateor its salts in its single enantiomeric form or as a racemate;3-[4-{2-(5-Cyclopropyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy)ethoxy}phenyl]-2-ethoxypropanoicacid or its salts in its single enantiomeric form or as a racemate;Ethyl6-[5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl{4-(1-ethyloxycarbonylbutoxyl)phenyl}carboxamido]hexanoateor its salts in its single enantiomeric form or as a racemate;6-[4-(1-Carboxybutoxy)phenyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido]hexanoicacid or its salts in its single enantiomeric form or as a racemate;Ethyl3-[4-{1,5-dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl(4-fluorobenzyl)carboxamido}phenyl]-2-ethoxypropanoateor its salts in its single enantiomeric form or as a racemate;3-[4-{1,5-Dimethyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl(4-fluorobenzyl)carboxamido}phenyl]-2-ethoxypropanoicacid or its salts in its single enantiomeric form or as a racemate;Ethyl2-(4-[5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy-methyl{4-(4-ethyloxycarbonylphenyl)butyl}carboxamido]phenoxy)pentanoateor its salts in its single enantiomeric form or as a racemate;2-[4-{4-(4-Carboxyphenyl)butyl(5-ethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxymethyl)carboxamido}phenoxy]pentanoicacid or its salts in its single enantiomeric form or as a racemate;
 5. Acompound according to claim 1 wherein the pharmaceutically acceptablesalt is selected from the group consisting of Li, Na, K, Ca, Mg, Fe, Cu,Zn, Al, Mn; organic bases selected from N,N′-diacetylethylenediamine,betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine,piperidine, procaine, theobromine, glycinol, diethylamine,triethylamine, trimethylamine, tripropylamine, tromethamine, adamentylamine, diethanolamine, meglumine, ethylenediamine,N,N′-diphenylethylenediamine, N,N′-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine,metformin, benzylamine, phenylethylamine, thiamine, aminopyrimidine,aminopyridine, purine or spermidine; chiral bases like alkylphenylamineor phenyl glycinol; salts of natural amino acids selected from glycine,alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine,cysteine, methionine, proline, hydroxy proline, histidine, ornithine,lysine, arginine, serine, threonine, phenylalanine; unnatural aminoacids selected from D-isomers or substituted amino acids; guanidine,substituted guanidine wherein the substituents are selected from nitro,amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts.Salts include acid addition salts where appropriate which are,sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides,acetates, tartrates, maleates, citrates, succinates, palmoates,methanesulfonates, benzoates, salicylates, hydroxynaphthoates,benzenesulfonates, ascorbates, glycerophosphates or ketoglutarates.
 6. Aprocess for the preparation of compound of formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ and R⁷together represent a bond; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl alkoxy, aryl, alkanoyl alkanoyloxy, aroyl aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; R³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Z represents oxygen; Ar represents substituted orunsubstituted, divalent, single or fused, aromatic, heteroaromatic orheterocyclic group; G represents O or S; X represents O, NHR⁵,—CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl, heteroaralkyl groups or(C₁-C₁₂)alkylcarboxylic acid and its derivatives; Y represents CHR⁷;where R⁷ forms a bond together with the adjacent group R¹; m and p areintegers ranging from 0-4; n is an integer in the range of 1-4; Arepresents pyrazolopyrimidine or imidazolopyrimidine of the formulagiven below:

where R¹ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives, which comprises: a)reacting the compound of formula (IIIa)A-G-(CH₂)_(n)—X—Ar—CHO  (IIIa) where all symbols are as defined abovewith a compound of formula (IIIb)

where R¹¹ represents (C₁₋₆)alkyl, R represents substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl orheteroaralkyl and all other symbols are as defined earlier to yieldcompound of general formula (I) where R² represents substituted orunsubstituted groups selected from alkoxy, aryloxy, aralkoxy,heteroaryloxy, heteroaralkoxy and all other symbols are as definedabove; b) reacting the compound of formula (IIIa)A-G-(CH₂)_(n)—X—Ar—CHO  (IIIa) where all symbols are as defined abovewith Wittig reagent to yield a compound of formula (I) where all symbolsare as defined above; or c) reacting the compound of formula (IIIc)B—H  (IIIc) where B represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

wherein Q represents O or S and all other symbols are as defined abovewith compound of general formula (IIId)

where L¹ is a leaving group; R¹ and R⁷ together represent a bond and allother symbols are as defined above to yield compound of formula (I)where all symbols are as defined above; or d) reacting the compound offormula (IIIa)A-G-(CH₂)_(n)—X—Ar—CHO  (IIIa) where all symbols are as defined abovewith a compound of formula (IIIe)

where R¹ represents hydrogen atom and all other symbols are as definedabove; or e) reacting the compound of formula (IIIg)A-G-(CH₂)_(n)-L¹  (IIIg) where L¹ represents a leaving group and allother symbols are as defined above with compound of formula (IIIf)

where R¹ and R⁷ together represent a bond and all other symbols are asdefined above; or f) reaction of compound of general formula (IIIh)A-Hal  (IIIh) A is as defined above and Hal represents halogen atom withcompound of formula (IIIi)

where all symbols are as defined above; or g) reacting the of compoundof general formula (IIIj)A-G-(CH₂)_(n)—OH  (IIIj) where all symbols are as defined above with acompound of general formula (IIIf)

where all symbols are as defined above; or h) reacting the compound offormula (IIIk)A-G-(CH₂)_(n)—X—Ar—CH₂—P⁺Ph₃Hal⁻  (IIIk) where all symbols are asdefined above with a compound of formula (IIIl)

where R represents substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and where R³ is asdefined earlier excluding hydrogen to yield compound of general formula(I) where R² represents substituted or unsubstituted groups selectedfrom alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and allother symbols are as defined above i) reacting the compound of formula(IIIc)B—H  (IIIc) where B represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

wherein Q represents O or S and all other symbols are as defined abovewith compound of general formula (IIIm)

where all symbols are as defined above; j) converting the compounds offormula (I) obtained in any of the processes described above intopharmaceutically acceptable salts or pharmaceutically acceptablesolvates by conventional methods.
 7. A process for the preparation ofcompound of formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; R³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Z represents oxygen; Ar represents substituted orunsubstituted, divalent, single or fused, aromatic, heteroaromatic orheterocyclic group; G represents O or S; X represents O, NHR⁵,—CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl, heteroaralkyl groups or(C₁-C₁₂)alkylcarboxylic acid and its derivatives; Y represents CHR⁷;where R⁷ represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy,substituted or unsubstituted aralkyl group; m and p are integers rangingfrom 0-4; n is an integer in the range of 1-4; A representspyrazolopyrimidine or imidazolopyrimidine of the formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives, which comprises: a)reducing the compound of the formula (IVa)

which represents a compound of formula (I) where R¹ and R⁷ togetherrepresent a bond and Z represents oxygen atom and all other symbols areas defined above to yield a compound of the general formula (I) where R¹and R⁵ each represent hydrogen atom and all other symbols are as definedabove; or b) reacting the compound of formula (IVb)

where L¹ is a leaving group, R³ is as defined earlier excluding hydrogenand all other symbols are as defined earlier with an alcohol of generalformula (IVc),R—OH  (IVc) where R represents substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and allother symbols are as defined earlier to yield compound of generalformula (I) where R² represents substituted or unsubstituted groupsselected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxyand all other symbols above; or c) reacting the compound of formula(IIIg)A-G-(CH₂)_(n)-L¹  (IIIg) where all symbols are as defined above withcompound of formula (IIIf)

where all symbols are as defined above; or d) reacting the compound ofgeneral formula (IIIj)A-G-(CH₂)_(n)—OH  (III) where all symbols are as defined above with acompound of general formula (IIIf)

where all symbols are as defined above; or e) reacting the compound offormula (IVd),

which represents a compound of formula (I), when R² represents hydroxygroup and all other symbols are as defined above with a compound offormula (IVe)R-L²  (IVe) where R represents substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and L²is a halogen atom to yield compound of general formula (I) where R²represents substituted or unsubstituted groups selected from alkoxy,aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all other symbolsare as defined above; or f) reacting the compound of general formula(IIIh)A-Hal  (IIIh) where Hal represents halogen atom and A is as definedearlier with the compound of formula (IIIi)

where all other symbols are as defined above; or g) reacting thecompound of general formula (IIIc)B—H  (IIIc) where B represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

wherein Q represents O or S and all other symbols are as defined abovewith compound of general formula (IIIm)

where symbols are as defined above; or h) reacting the compound of thegeneral formula (IIIa)A-G-(CH₂)_(n)—X—Ar—CHO  (IIIa) where all symbols are as defined abovewith a compound of formula (IIIe)

where R¹ represents hydrogen atom and all other symbols are as definedabove; or i) reacting the compound of the general formula (IIIc)B—H  (IIIc) where B represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

wherein Q represents O or S and all other symbols are as defined abovewith compound of general formula (IIId)

where L¹ is a leaving group and all other symbols are as defined above;or j) converting the compound of formula (IVf)

where all symbols are as defined above to a compound of formula (I)where all symbols are as defined above; or k) reacting the compound offormula (IVg)

where R³ is as defined above excluding hydrogen and all other symbolsare as defined above with a compound of formula (IVc)R—OH  (IVc) where R represents substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and L²is a halogen atom to yield compound of general formula (I) where R²represents substituted or unsubstituted groups selected from alkoxy,aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all other symbolsare as defined above; or l) converting the compounds of formula (I)obtained in any of the processes described above into pharmaceuticallyacceptable salts, or pharmaceutically acceptable solvates.
 8. A processfor the preparation of compound of formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; R³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Z represents oxygen; Ar represents substituted orunsubstituted, divalent, single or fused, aromatic, heteroaromatic orheterocyclic group; G represents O or S; X represents NHR⁵,—CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵represents hydrogen or substituted or unsubstituted groups selected fromalkyl aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl, heteroaralkyl groups or(C₁-C₁₂)alkylcarboxylic acid and its derivatives; Y represents O, S,NR⁶; where R⁶ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; m and p are integers ranging from 0-4; n is an integer in therange of 1-4; A represents pyrazolopyrimidine or imidazolopyrimidine ofthe formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives, which comprises: a)reacting the compound of formula (Va)

where all symbols are as defined above with compound of formula (Vb)

where L¹ is a leaving group and all other symbols are as defined above;or b) reacting the compound of general formula (IIIc)B—H  (IIIc) where B represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

wherein Q represents O or S and all other symbols are as defined abovewith compound of general formula (IIId)

where L¹ is a leaving group and all other symbols are as defined above;or c) reacting the compound of formula (Vc)A-G-(CH₂)_(n)—CO-L¹  (Vc) where L¹ represents a leaving group and allother symbols are as defined above with compound of formula (IIIf)

where all symbols are as defined above; or d) reacting the compound ofgeneral formula (IIIh)A-Hal  (IIIh) where A is as defined above and Hal represents halogenatom with the compound of formula (IIIi)

where all symbols are as defined above; or e) reacting the compound offormula (Vd)A-G-(CH₂)_(n)—COOH  (Vd) where all symbols are as defined above with acompound of general formula (IIIf)

where all symbols are as defined above; or f) reacting the compound ofgeneral formula (IIIc)B—H  (IIIc) where B represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

wherein Q represents O or S and all other symbols are as defined abovewith compound of general formula (IIIm)

where all symbols are as defined above; or g) converting the compound offormula (IVf)

where all symbols are as defined above to a compound of formula (I)where all symbols are as defined above; or h) reacting the compound ofgeneral formula (IIIj)A-G-(CH₂)_(n)—OH  (IIIj) where A, G and n are as defined above with acompound of general formula (IIIf)

where all symbols are as defined above; or i) converting the compoundsof formula (I) obtained in any of the processes described above intopharmaceutically acceptable salts, or pharmaceutically acceptablesolvates.
 9. A process for the preparation of compound of formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl arylaminocarbonyl groups; R³represents hydrogen; Z represents oxygen; Ar represents substituted orunsubstituted, divalent, single or fused, aromatic, heteroaromatic orheterocyclic group; G represents O or S; X represents O, NHR⁵,—CO(C₂)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl, heteroaralkyl groups or(C₁-C₁₂)alkylcarboxylic acid and its derivatives; Y represents O, S, NR⁶or CHR⁷; where R⁶ represents hydrogen or substituted or unsubstitutedgroups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; R⁷ represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R¹; m and p are integers ranging from 0-4; n is aninteger in the range of 1-4; A represents pyrazolopyrimidine orimidazolopyrimidine of the formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkylaralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives, which comprises,hydrolysing a compound of formula (I) described in any of the claims 5,6 and 7, wherein R³ represents substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups and all other symbols are as defined above byconventional methods.
 10. A process for the preparation of compound offormula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; R³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Z represents NR⁴, where R⁴ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl or heteroaralkyl groups or R³ and R⁴ together may form asubstituted or unsubstituted 5 or 6 membered cyclic structure containingcarbon atoms, a nitrogen atom and which may optionally contain one ortwo additional heteroatoms selected from oxygen, sulfur or nitrogen; Arrepresents substituted or unsubstituted, divalent, single or fused,aromatic, heteroaromatic or heterocyclic group; G represents O or S; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—,—(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl,heteroaralkyl groups or (C₁-C₁₂)alkylcarboxylic acid and itsderivatives; Y represents O, S, NR⁶ or CHR⁷; where R⁶ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷ represents hydrogenatom, halogen, hydroxy, alkyl, alkoxy, substituted or unsubstitutedaralkyl group or forms a bond together with the adjacent group R¹; m andp are integers ranging from 0-4; n is an integer in the range of 1-4; Arepresents pyrazolopyrimidine or imidazolopyrimidine of the formulagiven below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoylaroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives, which comprises: a)reacting a compound of formula (I) where all symbols are as definedabove and Y represent oxygen or ZR³ represents a halogen atom or COZR³represents a mixed anhydride group with appropriate amines of theformula NHR³R⁴, where R³ and R³ are as defined above and if desired; b)converting the compounds of formula (I) obtained above intopharmaceutically acceptable salts or pharmaceutically acceptablesolvates by conventional methods.
 11. An intermediate of formula (IIIa)A-G-(CH₂)_(n)—X—Ar—CHO  (IIIa) their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates where Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Grepresents O or S; X represents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl, heteroaralkyl groups or (C₁-C₁₂)alkylcarboxylic acid and itsderivatives; m and p are integers ranging from 0-4; n is an integer inthe range of 1-4; A represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.
 12. An intermediate offormula (IVb)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where L² is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like; R¹ represents hydrogen atom,halogen, hydroxy, alkyl, alkoxy, acyl, substituted or unsubstitutedaralkyl groups; R³ represents hydrogen or substituted or unsubstitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl or heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups or R³ andR⁴ together may form a substituted or unsubstituted 5 or 6 memberedcyclic structure containing carbon atoms, a nitrogen atom and which mayoptionally contain one or two additional heteroatoms selected fromoxygen, sulfur or nitrogen; Ar represents substituted or unsubstituted,divalent, single or fused, aromatic, heteroaromatic or heterocyclicgroup; G represents O or S; X represents O, NHR⁵,—CO(CH₂)_(p)NR⁵(CH₂)_(m)—, (CH₂)_(p)O, —(CH₂)_(p)NR⁵CO—; where R⁵represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl, heteroaralkyl groups or(C₁-C₁₂)alkylcarboxylic acid and its derivatives; Y represents O, S, NR⁶or CHR⁷; where R⁶ represents hydrogen or substituted or unsubstitutedgroups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; R⁷ represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R¹; m and p are integers ranging from 0-4; n is aninteger in the range of 1-4; A represents pyrazolopyrimidine orimidazolopyrimidine of the formula given below:

where R⁸ and R⁹, R¹⁰ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.
 13. An intermediate offormula (IVf)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; Arrepresents substituted or unsubstituted, divalent, single or fused,aromatic, heteroaromatic, or heterocyclic group; G represents O or S; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, (CH₂)_(p)O, —(CH₂)NR⁵CO—;where R⁵ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl, heteroaralkylgroups or (C₁-C₁₂)alkylcarboxylic acid and its derivatives; Y representsO, S, NR⁶ or CHR⁷; where R⁶ represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl orheteroaralkyl groups; R⁷ represents hydrogen atom, halogen, hydroxy,alkyl, alkoxy, substituted or unsubstituted aralkyl group or forms abond together with the adjacent group R¹; m and p are integers rangingfrom 0-4; n is an integer in the range of 1-4; A representspyrazolopyrimidine or imidazolopyrimidine of the formula given below:

where and R⁹, R¹⁰ when attached to carbon atom may be same or differentand represent hydrogen, halogen, hydroxy, nitro, cyano, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.
 14. An intermediate offormula (IVg)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R³represents-hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Grepresents O or S; X represents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,(CH₂)_(p)O, —(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl, heteroaralkyl groups or (C₁-C₁₂)alkylcarboxylic acid and itsderivatives; Y represents O, S, NR⁶ or CHR⁷; where R⁶ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷ represents hydrogenatom, halogen, hydroxy, alkyl, alkoxy, substituted or unsubstitutedaralkyl group; m and p are integers ranging from 0-4; n is an integer inthe range of 1-4; A represents pyrazolopyrimidine or imidazolopyrimidineof the formula given below:

where R⁸ and R⁹, R₁₀ when attached to carbon atom may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor substituted or unsubstituted groups selected from alkyl cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, aminoalkyl alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R⁹ and R¹⁰ whenattached to nitrogen atom represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl,aroyl, alkanoyloxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.
 15. An intermediate offormula (IIIf)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where R¹ representshydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl groups; R² represents hydrogen, hydroxy, halogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups; R³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl carboxyalkyl, alkanoyl, aroyl, aralkanoylheterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—,—(CH₂)_(p)NR⁵CO—; where R represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroarylheteroaralkyl groups or (C₁-C₁₂)alkylcarboxylic acid and itsderivatives; Y represents O, S, NR⁶ or CHR⁷; where R⁶ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷ represents hydrogenatom, halogen, hydroxy, alkyl, alkoxy, substituted or unsubstitutedaralkyl group or forms a bond together with the adjacent group R¹; m andp are integers ranging from 0-4.
 16. A process for preparing thecompound of formula (IIIf)

wherein all the symbols are as defined in claim 15, which comprises: a.reducing a compound of formula (IIIf-1)

where all symbols are as defined in claim 15, in the presence of gaseoushydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C or a mixturethereof. The reaction is carried out in the presence of a solventselected from dioxane, acetic acid, ethyl acetate, alcohol like methanolor ethanol or a mixture thereof. A pressure between atmospheric pressureand 40 to 80 psi is employed. The catalyst used is preferably 5-10% Pd/Cand the amount from 5-100% w/w. Alternatively the reaction can becarried out by employing metal solvent reduction selected from magnesiumor samarium in alcohol or sodium amalgam in alcohol, preferably methanolto yield a compound of formula (IIIf)

where all symbols are as defined earlier or b. reacting a compound offormula (IIIf-2)

where all symbols are as defined earlier with a compound of formula(IIIf-3)R⁵—NH₂  IIIf-3 where R⁵ represents alkyl group using a solvent selectedfrom CH₂Cl₂, CHCl₃, chlorobenzene, benzene, THF, in the presence ofcatalyst selected from p-toluenesulfonic acid, methanesulfonic acid,TFA, TfOH, BF₃—OEt₂ or in the presence of activated molecular sieves ata temperature in the range of 10° C. to 100° C., preferably at atemperature in the range from 10° C. to 60° C. for a period in the rangeof 1 h to 48 h. The imine thus obtained is reduced in the presence ofNa(CN)BH₃—HCl to obtain the compound of formula (IIIf) where R⁵represents alkyl group and all other symbols are as defined earlier. Orc. Conversion of the compound of formula (IIIf-4)

where R⁵ represents hydrogen and all other symbols as defined earlier,in the presence of a solvent selected from MeOH, EtOH or i-PrOH usinghydroxylamine hydrochloride, in the presence or absence of a promoterselected from NaOAc, KOAc or a mixture thereof. The reaction is carriedout at a temperature in the range of room temperature to the refluxtemperature of the solvent used for a period in the range of 2 h to 24h, preferably in the range 2 h to 12 h. The imine product thus obtainedabove may be reduced by using Na(CN)BH₃—HCl to obtain the compound offormula (IIIf) wher R⁵ represents hydrogen and all other symbols are asdefined earlier. Or d. reducing the compound of formula (IIIf-5)

to a compound of formula (IIIf) where R⁵ represents hydrogen and allother symbols are as defined earlier, in the presence of gaseoushydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C or a mixturethereof. The reaction is carried out in the presence of a solventselected from dioxane, acetic acid, ethyl acetate, alcohol like methanolor ethanol or a mixture thereof. A pressure between atmospheric pressureand 40 to 80 psi is employed. The catalyst used is preferably 5-10% Pd/Cand the amount from 5-100% w/w. Alternatively the reaction can becarried out by employing metal solvent reduction selected from magnesiumor samarium in alcohol or sodium amalgam in alcohol, preferablymethanol. Or e. i. diazotization of the compound of formula (IIIf-6)

where Z is as defined earlier excluding NH and all other symbols are asdefined earlier to obtain compound of formula (IIIf-7)

where R² represents substituted or unsubstituted groups selected fromalkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all othersymbols are as defined earlier is carried out using a diazotizing agentselected from sodium nitrite, isoamyl nitrite, potassium nitrite orammonium nitrite under aqueous acidic conditions using an acid selectedfrom sulfuric acid, HCl or acetic acid, in an organic solvent selectedfrom an alcohol like methanol, ethanol or propanol; 1,4-dioxane, THF oracetone. Etherifying the residue obtained using an alkylating agentselected from alkyl sulfate like diethyl sulphate or dimethylsulphate;alkyl halide like ethyl iodide or methyliodide, in a solvent selectedfrom a hydrocarbon like toluene or benzene or DMF, DMSO or methylisobutyl ketone (MIBK), in the presence of a alkali base selected fromsodium carbonate, potassium carbonate, sodium methoxide, sodium hydrideor potassium hydride. ii. The compound of formula (IIIf-7) is convertedto a compound of formula (IIIf) where R⁵ represents hydrogen atom andall other symbols are as defined earlier in the presence of gaseoushydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C or a mixturethereof. The reaction is carried out in the presence of a solventselected from dioxane, acetic acid, ethyl acetate, alcohol like methanolor ethanol or a mixture thereof. A pressure between atmospheric pressureand 40 to 80 psi is employed. The catalyst used is preferably 5-10% Pd/Cand the amount from 5-100% w/w. Alternatively the reaction can becarried out by employing metal solvent reduction selected from magnesiumor samarium in alcohol or sodium amalgam in alcohol, preferablymethanol. Or f. i. reacting a compound of formula (IIIb)

where all symbols are as defined earlier, with a compound of formula(IIIf-9)

where R¹² represents (C₁-C₆)alkyl group to yield compound of formula(IIIf-10)

where Z is as defined earlier excluding NH and all symbols are asdefined earlier, is carried out in the presence of a base like a metalhydride like NaH or KH; organolithiums like CH₃Li or BuLi; alkoxideslike NaOMe, NaOEt or t-BuO⁻K⁺ or a mixture thereof. The reaction iscarried out in the presence of a solvent selected from diethyl ether,THF, dioxane, DMF, DMSO, DME, dimethyl acetamide or a mixture thereof inthe presence or absence of HMPA as a cosolvent at a temperature in therange of −78° C. to 50° C., preferably at a temperature in the range of−10° C. to 30° C. ii. The compound of formula (IIIf-10) is reduce tocompound of formula (IIIf-2)

where all symbols are as defined earlier in the presence of gaseoushydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C or a mixturethereof. The reaction is carried out in the presence of a solventselected from dioxane, acetic acid, ethyl acetate, alcohol like methanolor ethanol or a mixture thereof. A pressure between atmospheric pressureand to 80 psi is employed. The catalyst used is preferably 5-10% Pd/Cand the amount from 5-50% w/w. Alternatively the reaction can be carriedout by employing metal solvent reduction selected from magnesium, iron,tin or samarium in alcohol or sodium amalgam in alcohol, preferablymethanol. iii. reacting a compound of formula (IIIf-2)R⁵—NH₂  IIIf-3 where R⁵ is as defined earlier using a solvent selectedfrom CH₂Cl₂, CHCl₃, chlorobenzene, benzene, THF, in the presence ofcatalyst selected from p-toluenesulfonic acid, methanesulfonic acid,TFA, TfOH, BF₃—OEt₂ or in the presence of activated molecular sieves ata temperature in the range of 10° C. to 100° C., preferably at atemperature in the range from 10° C. to 60° C. for a period in the rangeof 1 h to 48 h. The imine thus obtained is reduced in the presence ofNa(CN)BH₃—HCl to obtain the compound of formula (IIIf) where R⁵represents alkyl group and all other symbols are as defined earlier. 17.An intermediate of the formula (IIId)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates where L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate; R¹ represents hydrogen atom, halogen,hydroxy, alkyl, alkoxy, acyl, substituted or unsubstituted aralkylgroups; R² represents hydrogen, hydroxy, halogen, substituted orunsubstituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy,heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl alkylaminocarbonyl,arylaminocarbonyl groups; R³ represents hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl or heteroaralkyl groups; Z represents oxygen orNR⁴, where R⁴ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, hydroxyalkyl carboxyalkyl, alkanoyl,aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups orR³ and R⁴ together may form a substituted or unsubstituted 5 or 6membered cyclic structure containing carbon atoms, a nitrogen atom andwhich may optionally contain one or two additional heteroatoms selectedfrom oxygen, sulfur or nitrogen; Ar represents substituted orunsubstituted, divalent, single or fused, aromatic, heteroaromatic orheterocyclic group; X represents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—,—(CH₂)_(p)O—, —(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen orsubstituted or unsubstituted groups selected from alkyl, aryl, aralkyl,hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl,heteroaryl or heteroaralkyl groups; Y represents O, S. NR⁶ or CHR⁷;where R⁶ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl,alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkylgroups; R⁷ represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R¹; n is an integer in the range of 1-4; m and p areintegers ranging from 0-4.
 18. A process for preparation of the compoundof formula (IIId)

where all the symbols are as defined in claim 17, which comprisesreacting the compound of formula (IIIf)

where X represents NHR⁵ and all other symbols are as defined earlierwith compound of formula (IIId-1)L¹-(CH₂)_(n)—CO-L²  (IIId-1) where L¹ and n are as defined earlier andL² represents halogen, in the presence of a solvent selected from DCM,DCE, THF, DMF, DMSO, DME or a mixture thereof. The reaction is carriedout in an inert atmosphere maintained by using inert a gase like N₂, Aror He, in the presence of a base selected from triethyl amine, lutidine,collidine or a mixture thereof at a temperature in the range of −20°C.-120° C. for a period in the range oft to 48 hours, preferably from 2to 12 hours to yield a compound of formula (IIId) where all symbols areas defined earlier.
 19. An intermediate of the formula (IIId)

their derivatives, their analogs, their tautomeric forms, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates where L¹ is a leaving group such ashalogen, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate; R¹ represents hydrogen; R² representshydrogen, hydroxy, halogen, substituted or unsubstituted groups selectedfrom alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl,alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonylgroups; R³ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkyl,aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—,—(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen or substituted orunsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Y represents O, S, NR⁶ or CHR⁷; where R⁶represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, substitutedor unsubstituted aralkyl group or forms a bond together with theadjacent group R¹; n is an integer in the range of 1-4; m and p areintegers ranging from 0-4.
 20. A process for preparation of the compoundof formula (IIId)

where all the symbols are as defined in claim 19, which comprisesreacting the compound of formula (IIIf)

where X represents NHR⁵ and all other symbols are as defined above withcompound of formula (IIId-1)L¹-(CH₂)_(n)—CO-L²  (IIId-1) where L¹ and n are as defined earlier andL² represents halogen, in the presence of a solvent selected from DCM,DCE, THF, DMF, DMSO, DME or a mixture thereof. The reaction is carriedout in an inert atmosphere maintained by using inert a gase like N₂, Aror He, in the presence of a base selected from triethyl amine, lutidine,collidine or a mixture thereof at a temperature in the range of −20°C.-120° C. for a period in the range of 1 to 48 hours, preferably from 2to 12 hours to yield a compound of formula (IIId) where all symbols areas defined earlier.
 21. An intermediate of the formula (IIId)

their derivatives, their analogs, their tautomeric forms, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates where L¹ is a leaving group such ashalogen, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate; R¹ represents hydrogen; R² representshydrogen, hydroxy, halogen, substituted or unsubstituted groups selectedfrom alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl,alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonylgroups; R³ represents hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups; Z represents oxygen or NR⁴, where R⁴ representshydrogen or substituted or unsubstituted groups selected from alkylaryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl,heterocyclyl, heteroaryl or heteroaralkyl groups or R³ and R⁴ togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, a nitrogen atom and which may optionallycontain one or two additional heteroatoms selected from oxygen, sulfuror nitrogen; Ar represents substituted or unsubstituted, divalent,single or fused, aromatic, heteroaromatic or heterocyclic group; Xrepresents O, NHR⁵, —CO(CH₂)_(p)NR⁵(CH₂)_(m)—, —(CH₂)_(p)O—,—(CH₂)_(p)NR⁵CO—; where R⁵ represents hydrogen or substituted orunsubstituted groups selected from alkyl aryl, aralkyl, hydroxyalkyl,carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Y represents O, S, NR⁶ or CHR⁷; where R⁶represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl,aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R⁷represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, substitutedor unsubstituted aralkyl group or forms a bond together with theadjacent group R¹; n is an integer in the range of 1-4; m and p areintegers ranging from 0-4.
 22. A process for preparation of the compoundof formula (IIId)

where all the symbols are as defined in claim 19, which comprisesreacting the compound of formula (IIIf)

where X represents NHR⁵ and all other symbols are as defined above withcompound of formula (IIId-1)L¹-(CH₂)_(n)—CO-L²  (IIId-1) where L¹ and n are as defined earlier andL² represents halogen, in the presence of a solvent selected from DCM,DCE, THF, DMF, DMSO, DME or a mixture thereof. The reaction is carriedout in an inert atmosphere maintained by using inert a gase like N₂, Aror He, in the presence of a base selected from triethyl amine, lutidine,collidine or a mixture thereof at a temperature in the range of −20°C.-120° C. for a period in the range of 1 to 48 hours, preferably from 2to 12 hours to yield a compound of formula (IIId) where all symbols areas defined earlier.
 23. A compound according to claim 1, wherein whenthe groups represented by R⁵ are substituted, the substituents areselected from halogen, hydroxy, nitro or substituted or unsubstitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aralkyl, aryloxy, aralkoxy, aralkoxyalkyl, heterocyclyl, heteroaryl,heteroaralkyl, hydroxyalkyl, amino, arylamino, aminoalkyl, alkylamino,alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives; sulfonic acid or its derivatives.
 24. A pharmaceuticalcomposition which comprises a compound of formula (I)

as defined in claim 1 and a pharmaceutically acceptable carrier,diluent, excipient or solvate.
 25. A pharmaceutical composition asclaimed in claim 24, in the form of a tablet, capsule, powder, syrup,solution or suspension.
 26. A composition which comprises a compound offormula (I) as defined in claim 1 or a compound as claimed in claim 4and an HMG CoA reductase inhibitor; cholesterol absorption inhibitor;antiobesity drug; lipoprotein disorder treatment drug; hypoglycemicagent; insulin; biguanide; sulfonylurea; thiazolidinedione; dual PPARαand γ agonis or a mixture thereof.
 27. A method of preventing ortreating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis,obesity, impaired glucose tolerance, atherosclerosis, leptin resistance,insulin resistance or diseases in which insulin resistance is theunderlying pathophysiological mechanism comprising administering acompound of formula (I) as defined in claim 1 or a compound as claimedin claim 4 or a pharmaceutical composition according to claim 24 or 25to a patient in need thereof.
 28. A method according to claim 27,wherein the disease is type II diabetes, impaired glucose tolerance,dyslipidemia, disorders related to Syndrome X including hypertension,obesity, insulin resistance, coronary artery disease and othercardiovascular disorders; renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, nephropathy, disorders to related endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), dementia,diabetic complications, inflammatory bowel diseases, myotonic dystrophy,pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer orosteoporosis or as inflammatory agents.
 29. A method according to claim27, for the treatment and/or prophylaxis of disorders related toSyndrome X, which comprises administering an agonist of PPARα and/orPPARγ of formula (I) as claimed in claim 1 or a compound as claimed inclaim 4 or a pharmaceutical composition according to claim 24 or 25 to apatient in need thereof.
 30. A method of reducing total cholesterol,body weight, blood plasma glucose, triglycerides, LDL, VLDL or freefatty acids or increasing HDL in the plasma comprising administering acompound of formula (I), as defined in claim 1 or a compound as claimedin claim 4 or a pharmaceutical composition according to claim 24 or 25to a patient in need thereof.
 31. A method of preventing or treatinghyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity,impaired glucose tolerance, atherosclerosis, leptin resistance, insulinresistance, or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering to a patient inneed thereof an effective amount of a compound of formula (I) as definedin claim 1 or a compound as claimed in claim 4 or a pharmaceuticalcomposition according to claim 24 or 25 in combination/concomittant witha HMG CoA reductase inhibitor; cholesterol absorption inhibitor;antiobesity drug; lipoprotein disorder treatment drug; hypoglycemicagent; insulin; biguanide; sulfonylurea; thiazolidinedione; dual PPARαand γ agonis or a mixture thereof within such a period so as to actsynergistically.
 32. A method according to claim 31, wherein the diseaseis type II diabetes, impaired glucose tolerance, dyslipidemia, disordersrelated to Syndrome X such as hypertension, obesity, insulin resistance,coronary artery disease and other cardiovascular disorders; certainrenal diseases including glomerulonephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis, retinopathy,nephropathy, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS), dementia, diabeticcomplications, osteoporosis, inflammatory bowel diseases, myotonicdystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders,cancer or as inflammatory agents.
 33. A method according to claim 31,for the treatment and/or prophylaxis of disorders related to Syndrome Xwhich comprises administering to a patient in need thereof an agonist ofPPARα and/or PPARγ of formula (I) as claimed in claim 1 or a compound asclaimed in claim 4 or a pharmaceutical composition according to claim 24or 25 and a HMG CoA reductase inhibitor; cholesterol absorptioninhibitor; antiobesity drug; lipoprotein disorder treatment drug;hypoglycemic agent; insulin; biguanide; sulfonylurea; thiazolidinedione;dual PPARα and γ agonis or a mixture thereof within such a period as toact synergistically.
 34. A method of reducing plasma glucose,triglycerides, total cholesterol, LDL, VLDL or free fatty acids orincreasing HDL in the plasma, which comprises administering a compoundof formula (I) claimed in claim 1 or a compound as claimed in claim 4 ora pharmaceutical composition according to claim 24 or 25, incombination/concomittant with a HMG CoA reductase inhibitor; cholesterolabsorption inhibitor; antiobesity drug; lipoprotein disorder treatmentdrug; hypoglycemic agent; insulin; biguanide; sulfonylurea;thiazolidinedione; dual PPARα and γ agonis or a mixture thereof whichmay be administered together or within such a period as to actsynergistically together to a patient in need thereof.